Toll like receptor modulator compounds

ABSTRACT

The present disclosure relates generally to toll like receptor modulator compounds, such as diamino pyrido[3,2 D] pyrimidine compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR-8), and methods of making and using them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/496,283, filed on Apr. 25, 2017, which is a Continuation of U.S.application Ser. No. 15/059,070, filed on Mar. 2, 2016, now U.S. Pat.No. 9,670,205, issued on Jun. 6, 2017, which claims priority to U.S.Provisional Application Nos. 62/128,397, filed Mar. 4, 2015, and62/250,403, filed Nov. 3, 2015, all of which are incorporated herein intheir entireties for all purposes.

FIELD

This application relates generally to toll like receptor modulatorcompounds, including diamino pyrido[3,2 D] pyrimidine compounds, andpharmaceutical compositions which, among other things, modulatetoll-like receptors (e.g. TLR-8), and methods of making and using them.

BACKGROUND

The toll-like receptor (TLR) family plays a fundamental role in pathogenrecognition and activation of innate immunity. Toll-like receptor 8(TLR-8) is predominantly expressed by myeloid immune cells andactivation of this receptor stimulates a broad immunological response.Agonists of TLR-8 activate myeloid dendritic cells, monocytes,monocyte-derived dendridic cells and Kupffer cells leading to theproduction of proinflammatory cytokines and chemokines, such asinterleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosisfactor-alpha (TNF-α), and interferon-gamma (IFN-γ). Such agonists alsopromote the increased expression of co-stimulatory molecules such asCD8⁺ cells, major histocompatibility complex molecules (MAIT, NK cells),and chemokine receptors.

Collectively, activation of these innate and adaptive immune responsesinduces an immune response and provides a therapeutic benefit in variousconditions involving autoimmunity, inflammation, allergy, asthma, graftrejection, graft versus host disease (GvHD), infection, cancer, andimmunodeficiency. For example, with respect to hepatitis B, activationof TLR8 on professional antigen presenting cells (pAPCs) and otherintrahepatic immune cells is associated with induction of IL-12 andproinflammatory cytokines, which is expected to augment HBV-specific Tcell responses, activate intrahepatic NK cells and drive reconstitutionof antiviral immunity. See e.g. Wille-Reece, U. et al. J Exp Med 203,1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J.et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., JBiol Chem 288, 31715-31727 (2013).

Given the potential to treat a wide array of diseases, there remains aneed for novel modulators of toll like receptors, for example TLR-8.Potent and selective modulators of TLR-8 that have reduced potential foroff target liabilities are particularly desireable.

SUMMARY

The present disclosure provides a compound of Formula (J):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is N or CR¹⁰;    -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R⁴ is C₁₋₁₂ alkyl which is optionally substituted with 1 to 5        substituents independently selected from halogen, —OR^(a),        —NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur;    -   wherein each C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl, C₆₋₁₀        aryl, and 5 to 10 membered heteroaryl is optionally substituted        with 1 to 5 R²¹ groups;    -   R¹⁰ is selected from hydrogen, halogen, C₁₋₆alkyl, CN,        —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein C₁₋₆alkyl is        optionally substituted with 1 to 5 R²⁰ groups    -   each R²⁰ is independently selected from the group consisting of        halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a), and        OR^(a);    -   each R²¹ is independently selected from the group consisting of        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CN, —NR^(a)R^(b),        S(O)₁₋₂R^(a), and OR^(a); and    -   each R^(a) and R^(b) are independently selected from the group        consisting of hydrogen and C₁₋₆alkyl; wherein each C₁₋₆alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, hydroxyl, amino, 5 to 10 membered        heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3        heteroatoms selected from oxygen, nitrogen, and sulfur, and        C₁₋₆haloalkyl;    -   provided that when X is N, R¹ is Cl, R² is H and R³ is H then R⁴        is not CH₂CH₂OMe or CH₂CH₂SO₂Me.

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R⁴ is C₁₋₁₂ alkyl which is optionally substituted with 1 to 5        substituents independently selected from halogen, —OR^(a),        —NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur;    -   wherein each C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl, C₆₋₁₀        aryl, and 5 to 10 membered heteroaryl is optionally substituted        with 1 to 5 R²¹ groups;    -   each R²⁰ is independently selected from the group consisting of        halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a), and        OR^(a);    -   each R²¹ is independently selected from the group consisting of        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CN, —NR^(a)R^(b),        S(O)₁₋₂R^(a), and OR^(a); and    -   each R^(a) and R^(b) are independently selected from the group        consisting of hydrogen and C₁₋₆alkyl; wherein each C₁₋₆alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, hydroxyl, amino, 5 to 10 membered        heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3        heteroatoms selected from oxygen, nitrogen, and sulfur, and        C₁₋₆haloalkyl;    -   provided that when R¹ is Cl, R² is H and R³ is H then R⁴ is not        CH₂CH₂OMe or CH₂CH₂SO₂Me.

The present disclosure provides a compound of Formula (IV):

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl optionally        substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R¹¹ is selected from the group consisting of C₁₋₂ alkyl, C₃₋₆        cycloalkyl, and C₁₋₃ haloalkyl;    -   R¹² is selected from C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₃ alkyl group is        optionally substituted with 1 or 2 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   R¹³ is selected from C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₆ alkyl is        optionally substituted with 1 to 2 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   each R²⁰ is independently selected from the group consisting of        halogen, CN, —NR^(a)R^(b), and OR^(a); and    -   each R^(a) and R^(b) is independently selected from the group        consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl        is optionally substituted with 1 to 3 substituents independently        selected from halogen, —OH, and NH₂.

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition comprises one or more additional therapeutic agents.

In certain embodiments, a method of modulating TLR-8 is provided,comprising administering a compound of the present disclosure, or apharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, a method of treating or preventing a disease orcondition responsive to the modulation of TLR-8 is provided, comprisingadministering to an individual (e.g. a human) in need thereof atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In certainembodiments, the method of treating or preventing a disease or conditionresponsive to the modulation of TLR-8, comprises administering one ormore additional therapeutic agents.

In certain embodiments, a method of treating or preventing a viralinfection is provided, comprising administering to an individual (e.g. ahuman) in need thereof a therapeutically effective amount a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a hepatitis Bviral infection is provided, comprising administering to an individual(e.g. a human) in need thereof a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof. In certain embodiments, the method of treating orpreventing a hepatitis B viral infection comprises administering one ormore additional therapeutic agents. In certain embodiments, theindividual is a human infected with hepatitis B.

In certain embodiments, a method of treating or preventing a HIVinfection is provided, comprising administering to an individual (e.g. ahuman) in thereof a therapeutically effective amount a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof. Incertain embodiments, the method of treating or preventing a HIVinfection comprises administering one or more additional therapeuticagents. In certain embodiments, the individual is a human infected withHIV (e.g. HIV-1).

In certain embodiments, a method of treating a hyperproliferativedisease (e.g. cancer) is provided, comprising administering to anindividual (e.g. a human) in thereof a therapeutically effective amounta compound of the present disclosure, or a pharmaceutically acceptablesalt thereof. In certain embodiments, the method of treating ahyperproliferative disease (e.g. cancer) comprises administering one ormore additional therapeutic agents. In certain embodiments, theindividual is a human.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in medical therapy isprovided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in treating orpreventing a disease or condition responsive to the modulation of TLR-8,is provided. In certain embodiments, the disease or condition is a viralinfection.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in treating orpreventing hepatitis B, is provided.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a disease or condition responsiveto the modulation of TLR-8, is provided.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing hepatitis B, is provided.

Kits comprising the compounds, or pharmaceutically acceptable saltsthereof, or pharmaceutical compositions of the foregoing are alsoprovided. Articles of manufacture comprising a unit dose of thecompounds, or pharmaceutically acceptable salts thereof, of theforegoing are also provided. Methods of preparing compounds of thepresent disclosure are also provided.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

I. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience to indicate the point of attachment to a parent moiety;chemical groups may be depicted with or without one or more dasheswithout losing their ordinary meaning. A prefix such as “C_(u-v)” or(C_(u)-C_(v)) indicates that the following group has from u to v carbonatoms, where u and v are integers. For example, “C₁₋₆alkyl” indicatesthat the alkyl group has from 1 to 6 carbon atoms.

“Alkyl” is a linear or branched saturated monovalent hydrocarbon. Forexample, an alkyl group can have 1 to 10 carbon atoms (i.e.,(C₁₋₁₀)alkyl) or 1 to 8 carbon atoms (i.e., (Cis)alkyl) or 1 to 6 carbonatoms (i.e., (C₁₋₆ alkyl) or 1 to 4 carbon atoms (i.e., (C₁₋₄)alkyl).Examples of alkyl groups include, but are not limited to, methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl(—(CH₂)₇CH₃).

“Alkenyl” is a linear or branched monovalent hydrocarbon radical with atleast one carbon-carbon double bond. For example, an alkenyl group canhave 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), or 2 to 6 carbon atoms(i.e., C₂₋₆ alkenyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of suitable alkenyl groups include, but are not limited to,ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), 5-hexenyl(—CH₂CH₂CH₂CH₂CH═CH₂), and 3-hexenyl (—CH₂CH₂CH═CHCH₂CH₂).

“Alkynyl” is a linear or branched monovalent hydrocarbon radical with atleast one carbon-carbon triple bond. For example, an alkynyl group canhave 2 to 8 carbon atoms (i.e., C₂₋₈ alkyne) or 2 to 6 carbon atoms(i.e., C₂₋₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).Examples of alkynyl groups include, but are not limited to, acetylenyl(—C≡CH), propargyl (—CH₂C≡CH), and —CH₂—C≡C—CH₃.

The term “halo” or “halogen” as used herein refers to fluoro (—F),chloro (—Cl), bromo (—Br) and iodo (—I).

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl areindependently replaced by a halo substituent, which may be the same ordifferent. For example, C₁₋₈haloalkyl is a C₁₋₈alkyl wherein one or moreof the hydrogen atoms of the C₁₋₈alkyl have been replaced by a halosubstituent. Examples of haloalkyl groups include but are not limited tofluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

The term “heteroalkyl” as used herein refers to an alkyl as definedherein, wherein one or more of the carbon atoms of the alkyl arereplaced by an O, S, or NR^(q), wherein each R^(q) is independently H orC₁₋₆alkyl. For example, C₁₋₈heteroalkyl intends a heteroalkyl of one toeight carbons wherein one or more carbon atoms is replaced by aheteroatom (e.g., O, S, NR^(q), OH, SH or N(R^(q))₂), which may the sameor different. Examples of heteroalkyls include but are not limited tomethoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl andN,N′-dimethylpropylamine. A heteroatom of a heteroalkyl may optionallybe oxidized or alkylated. A heteroatom may be placed at any interiorposition of the heteroalkyl group or at a position at which the group isattached to the remainder of the molecule. Examples include, but are notlimited to, —CH₂OCH₃, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)—CH₃, —CH₂SCH₂CH₃,—S(O)CH₃, —CH₂CH₂S(O)₂CH₃, —CHCHOCH₃, —CH₂CHNOCH₃, —CHCHN(CH₃)CH₃,—CH₂NHOCH₃ and —CH₂OS(CH₃)₃

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis also to be understood that when reference is made to a certainatom-range membered aryl (e.g., 6-10 membered aryl), the atom range isfor the total ring atoms of the aryl. For example, a 6-membered arylwould include phenyl and a 10-membered aryl would include naphthyl and1, 2, 3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groupsinclude, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (toform for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (toform for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form forexample indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isto be understood that the point of attachment for a heteroaryl orheteroaryl multiple condensed ring system can be at any suitable atom ofthe heteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). It also to beunderstood that when a reference is made to a certain atom-rangemembered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atomrange is for the total ring atoms of the heteroaryl and includes carbonatoms and heteroatoms. For example, a 5-membered heteroaryl wouldinclude a thiazolyl and a 10-membered heteroaryl would include aquinolinyl. Exemplary heteroaryls include but are not limited topyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “cycloalkyl” refers to a single saturated or partiallyunsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e.,C₃₋₂₀ cycloalkyl), for example from 3 to 12 annular atoms, for examplefrom 3 to 10 annular atoms. The term “cycloalkyl” also includes multiplecondensed, saturated and partially unsaturated all carbon ring systems(e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).Accordingly, cycloalkyl includes multicyclic carbocyles such as abicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 annular carbon atoms). Therings of a multiple condensed ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from oxygen,nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl grouphas from 5 to about 20 annular atoms, for example from 3 to 12 annularatoms, for example from 5 to 10 annular atoms. Thus, the term includessingle saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or7-membered rings) having from about 1 to 6 annular carbon atoms and fromabout 1 to 3 annular heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the ring. The rings of the multiplecondensed ring system can be connected to each other via fused, spiroand bridged bonds when allowed by valency requirements. Heterocyclesinclude, but are not limited to, azetidine, aziridine, imidazolidine,morpholine, oxirane (epoxide), oxetane, piperazine, piperidine,pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran,tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine,N-bromopyrrolidine, N-chloropiperidine, and the like.

The term “oxo” as used herein refers to ═O.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition); andc) relieving the disease or condition, e.g., causing the regression ofclinical symptoms, ameliorating the disease state, delaying theprogression of the disease, increasing the quality of life, and/orprolonging survival.

A “compound of the present disclosure” includes compounds disclosedherein, for example a compound of the present disclosure includescompounds of Formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), and the compounds listed in Table 1. A compound of thepresent disclosure also includes compounds of Formula (J), (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (VI), (IVa), (IVb),(IVc), (IVd), the compounds of Examples 1-113, and the compounds listedin Tables 1 and 3. A compound of the present disclosure also includesthe compounds of Examples 1-118

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of AIDS is a method that reduces the probability ofdisease development in a given time frame and/or reduces extent of thedisease in a given time frame, when compared to not using the method.Such comparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming an individual's HIV⁺status and assessing the individual's T-cell count or other indicationof AIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present inindividuals with functioning immune systems but does occur in AIDSpatients). Development may also refer to disease progression that may beinitially undetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, in certain embodiments, the term“preventing HBV infection” refers to administering to a subject who doesnot have a detectable HBV infection an anti-HBV therapeutic substance.It is understood that the subject for anti-HBV preventative therapy maybe an individual at risk of contracting the HBV virus. Thus, in certainembodiments, the term “preventing HIV infection” refers to administeringto a subject who does not have a detectable HIV infection an anti-HIVtherapeutic substance. It is understood that the subject for anti-HIVpreventative therapy may be an individual at risk of contracting the HIVvirus.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease. The effectiveamount will vary depending on the compound, the disease, and itsseverity and the age, weight, etc., of the subject to be treated. Theeffective amount can include a range of amounts. As is understood in theart, an effective amount may be in one or more doses, i.e., a singledose or multiple doses may be required to achieve the desired treatmentendpoint. An effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable or beneficial result may be or isachieved. Suitable doses of any co-administered compounds may optionallybe lowered due to the combined action (e.g., additive or synergisticeffects) of the compounds.

As used herein, an “agonist” is a substance that stimulates its bindingpartner, typically a receptor. Stimulation is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Stimulation may be defined with respect to anincrease in a particular effect or function that is induced byinteraction of the agonist or partial agonist with a binding partner andcan include allosteric effects.

As used herein, an “antagonist” is a substance that inhibits its bindingpartner, typically a receptor. Inhibition is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Inhibition may be defined with respect to adecrease in a particular effect or function that is induced byinteraction of the antagonist with a binding partner, and can includeallosteric effects.

As used herein, a “partial agonist” or a “partial antagonist” is asubstance that provides a level of stimulation or inhibition,respectively, to its binding partner that is not fully or completelyagonistic or antagonistic, respectively. It will be recognized thatstimulation, and hence, inhibition is defined intrinsically for anysubstance or category of substances to be defined as agonists,antagonists, or partial agonists.

As used herein, “intrinsic activity” or “efficacy” relates to somemeasure of biological effectiveness of the binding partner complex. Withregard to receptor pharmacology, the context in which intrinsic activityor efficacy should be defined will depend on the context of the bindingpartner (e.g., receptor/ligand) complex and the consideration of anactivity relevant to a particular biological outcome. For example, insome circumstances, intrinsic activity may vary depending on theparticular second messenger system involved. Where such contextuallyspecific evaluations are relevant, and how they might be relevant in thecontext of the present disclosure, will be apparent to one of ordinaryskill in the art.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domestic animals

As used herein, modulation of a receptor includes agonism, partialagonism, antagonism, partial antagonism, or inverse agonism of areceptor.

The nomenclature used herein to name the subject compounds isillustrated in the Examples and elsewhere herein.

As used herein, “co-administration” includes administration of unitdosages of the compounds disclosed herein before or after administrationof unit dosages of one or more additional therapeutic agents, forexample, administration of the compound disclosed herein within seconds,minutes, or hours of the administration of one or more additionaltherapeutic agents. For example, in some embodiments, a unit dose of acompound of the present disclosure is administered first, followedwithin seconds or minutes by administration of a unit dose of one ormore additional therapeutic agents. Alternatively, in other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed by administration of a unit dose of a compound of thepresent disclosure within seconds or minutes. In some embodiments, aunit dose of a compound of the present disclosure is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of a compound of the presentdisclosure.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The compounds of described herein may be prepared and/or formulated aspharmaceutically acceptable salts. Pharmaceutically acceptable salts arenon-toxic salts of a free base form of a compound that possesses thedesired pharmacological activity of the free base. These salts may bederived from inorganic or organic acids or bases. For example, acompound that contains a basic nitrogen may be prepared as apharmaceutically acceptable salt by contacting the compound with aninorganic or organic acid. Non-limiting examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propylsulfonates, besylates,xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found in Remington:The Science and Practice of Pharmacy, 21^(st) Edition, LippincottWiliams and Wilkins, Philadelphia, Pa., 2006.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein also include salts derived from an appropriate base,such as an alkali metal (for example, sodium, potassium), an alkalineearth metal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X isC₁-C₄ alkyl). Also included are base addition salts, such as sodium orpotassium salts.

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomers, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosedcompounds also include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, 35S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. Substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds of Formula (I), can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. Thepresent disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centres of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any said compounds.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

A “prodrug” includes any compound that becomes a compound describedherein when administered to a subject, e.g., upon metabolic processingof the prodrug.

The terms “combination antiretroviral therapy” (“cART”) refers tocombinations or “cocktails” of antiretroviral medications used to treathuman viral infections, including HIV infections. As used herein, theterms “combination antiretroviral therapy” and “cART includecombinations and regimens often referred to as Highly ActiveAntiretroviral Therapy (HAART). HAART and cART combinations and regimenscommonly include multiple, often two or more, drugs such as nucleosidereverse transcriptase inhibitors (NRTIs), non-nucleoside reversetranscriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusioninhibitors, CCR5 agonists, and/or integrase inhibitors.

The terms “latent HIV reservoir”, “HIV latent reservoir”, “HIVreservoir”, “latent reservoir”, and “latent HIV infection” refer to acondition in which resting CD4+T lymphocytes or other cells are infectedwith HIV but are not actively producing HIV. The presently inactive HIVinfected cells are referred to as “latently infected cells”.Antiretroviral therapy (ART) can reduce the level of HIV in the blood toan undetectable level, while latent reservoirs of HIV continue tosurvive. When a latently infected cell is reactivated, the cell beginsto produce HIV (HIV replication).

II. COMPOUNDS

The present disclosure provides a compound of Formula (J):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is N or CR¹⁰;    -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R⁴ is C₁₋₁₂ alkyl which is optionally substituted with 1 to 5        substituents independently selected from halogen, —OR^(a),        —NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur;    -   wherein each C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl, C₆₋₁₀        aryl, and 5 to 10 membered heteroaryl is optionally substituted        with 1 to 5 R²¹ groups;    -   R¹⁰ is selected from hydrogen, halogen, C₁₋₆alkyl, CN,        —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein C₁₋₆alkyl is        optionally substituted with 1 to 5 R²⁰ groups each R²⁰ is        independently selected from the group consisting of halogen,        C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a), and OR^(a);    -   each R²¹ is independently selected from the group consisting of        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CN, —NR^(a)R^(b),        S(O)₁₋₂R^(a), and OR^(a); and    -   each R^(a) and R^(b) are independently selected from the group        consisting of hydrogen and C₁₋₆alkyl; wherein each C₁₋₆alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, hydroxyl, amino, 5 to 10 membered        heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3        heteroatoms selected from oxygen, nitrogen, and sulfur, and        C₁-6haloalkyl;    -   provided that when X is N, R¹ is Cl, R² is H and R³ is H then R⁴        is not CH₂CH₂OMe or CH₂CH₂SO₂Me.

In certain embodiments of Formula (J), X is CR¹⁰. In certain embodimentsof Formula (J), X is N.

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R⁴ is C₁₋₁₂ alkyl which is optionally substituted with 1 to 5        substituents independently selected from halogen, —OR^(a),        —NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur;    -   wherein each C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl, C₆₋₁₀        aryl, and 5 to 10 membered heteroaryl is optionally substituted        with 1 to 5 R²¹ groups;    -   each R²⁰ is independently selected from the group consisting of        halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a), and        OR^(a);    -   each R²¹ is independently selected from the group consisting of        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, CN, —NR^(a)R^(b),        S(O)₁₋₂R^(a), and OR^(a); and each R^(a) and R^(b) are        independently selected from the group consisting of H and        C₁₋₆alkyl; wherein each C₁₋₆alkyl is optionally substituted with        1 to 5 substituents independently selected from halogen,        hydroxyl, amino, 5 to 10 membered heteroaryl wherein the 5 to 10        membered heteroaryl has 1 to 3 heteroatoms selected from oxygen,        nitrogen, and sulfur, and C₁₋₆haloalkyl;    -   provided that when R¹ is Cl, R² is H and R³ is H then R⁴ is not        CH₂CH₂OMe or CH₂CH₂SO₂Me.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₈alkyl which is optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of halogen, —OR^(a),—NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),—NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),—NR^(a)S(O)₂R^(b), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6 memberedheterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; andwherein each C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl, C₆₋₁₀ aryl,and 5 to 10 membered heteroaryl is optionally substituted with 1 to 5R²¹ groups.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₆alkyl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of halogen, —OR^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —SR^(a), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3 to 6membered heterocyclyl, and C₆₋₁₀ aryl; wherein each C₃₋₆cycloalkyl, 3 to6 membered heterocyclyl, and C₆₋₁₀ aryl is optionally substituted with 1to 5 R²¹ groups. In certain embodiments of a compound of Formula (J) or(I), R⁴ is C₃₋₈ alkyl optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of halogen, —OR^(a),—C(O)OR^(a), —NR^(a)C(O)R^(b), —SR^(a), C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3to 6 membered heterocyclyl, and C₆₋₁₀ aryl; wherein each C₃₋₆cycloalkyl,3 to 6 membered heterocyclyl, and C₆₋₁₀ aryl is optionally substitutedwith 1 to 5 R²¹ groups.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₆alkyl optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halogen, —OR^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —SR^(a), —C₁₋₃haloalkyl, C₃₋₆cycloalkyl, 3 to 6membered heterocyclyl and C₆₋₁₀ aryl; wherein each C₃₋₆cycloalkyl andC₆₋₁₀ aryl is optionally substituted with 1 to 3 R²¹ groups. In certainembodiments of a compound of Formula (J) or (I), R⁴ is C₃₋₈ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halogen, —OR^(a), —C(O)OR^(a),—NR^(a)C(O)R^(b), —SR^(a), —C₁₋₃haloalkyl, C₃₋₆cycloalkyl, 3 to 6membered heterocyclyl and C₆₋₁₀ aryl; wherein each C₃₋₆cycloalkyl andC₆₋₁₀ aryl is optionally substituted with 1 to 3 R²¹ groups.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₆alkyl optionally substituted with 1 or 2 substituents independentlyselected halogen, —OR^(a), C(O)OR^(a), —C(O)NR^(a)R^(b), —SR^(a),C₁₋₃haloalkyl, C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl and C₆₋₁₀aryl; wherein each C₃₋₆cycloalkyl and C₆₋₁₀ aryl is optionallysubstituted with 1 to 3 R²¹ groups and wherein R^(a) and R^(b) are eachindependently hydrogen or C₁₋₄alkyl, wherein the C₁₋₄ alkyl isoptionally substituted with —NH₂, OH, or pyridyl. In certain embodimentsof a compound of Formula (J) or (I), R⁴ is C₃₋₈ alkyl which isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of halogen, —OR^(a), —C(O)OR^(a),—NR^(a)C(O)R^(b), —SR^(a), C₁₋₃haloalkyl, C₃₋₆cycloalkyl, 3 to 6membered heterocyclyl and C₆₋₁₀ aryl; wherein each C₃₋₆cycloalkyl andC₆₋₁₀ aryl is optionally substituted with 1 to 3 R²⁰ groups and whereinR^(a) and R^(b) are each independently hydrogen or C₁₋₄alkyl, whereineach C₁₋₄ alkyl is optionally substituted with —NH₂, OH, or pyridyl.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₆alkyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of OH, CF₃, —C(O)OH, —C(O)OCH₃,—C(O)NH₂, SCH₃, —C(O)NHCH₃, —C(O)NHCH₂CH₂NH₂, —C(O)NHCH₂CH₂OH,—C(O)NHCH₂-pyridyl, phenyl, tetrahydrofuranyl, and cyclopropyl. Incertain embodiments of a compound of Formula (J) or (I), R⁴ is C₃₋₈alkyl which is optionally substituted with 1 or 2 substituentsindependently selected from OH, CF₃, —C(O)OH, —C(O)OCH₃, SCH₃,—NHC(O)CH₃, —NHC(O)CH₂CH₂NH₂, —NHC(O)CH₂CH₂OH, —NHC(O)CH₂-pyridyl,phenyl, tetrahydrofuranyl, and cyclopropyl.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₃₋₆alkyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of OH, CF₃, —C(O)OH, —C(O)OCH₃,—C(O)NH₂, SCH₃, —C(O)NHCH₃, —C(O)NHCH₂CH₂NH₂, —C(O)NHCH₂CH₂OH, and—C(O)NHCH₂-pyridyl. In certain embodiments of a compound of Formula (J)or (I), R⁴ is C₃₋₆ alkyl which is optionally substituted with 1 or 2substituents independently selected from OH, CF₃, —C(O)OH, —C(O)OCH₃,SCH₃, —NHC(O)CH₃, —NHC(O)CH₂CH₂NH₂, —NHC(O)CH₂CH₂OH, —NHC(O)CH₂-pyridyl,phenyl, tetrahydrofuranyl, and cyclopropyl.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₁₋₆alkyl which is optionally substituted with OH. In certain embodiments ofa compound of Formula (J) or (I), R⁴ is C₃₋₈ alkyl which is optionallysubstituted with OH. In certain embodiments of a compound of Formula (J)or (I), R⁴ is C₃₋₈ alkyl which is substituted with —NHC(O)CH₃.

In certain embodiments of a compound of Formula (J) or (I), R⁴ is C₃₋₆alkyl which is optionally substituted with OH. In certain embodiments ofa compound of Formula (J) or (I), R⁴ is C₃₋₆ alkyl which is substitutedwith —NHC(O)CH₃.

In certain embodiments of a compound of Formula (J) or (I), R⁴ has atleast one chiral center. In certain embodiments, the at least one chiralcenter is in the S configuration. In certain embodiments, the at leastone chiral center is in the R configuration.

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of:

In certain embodiments of a compound of Formula (J) or (I), R⁴ isselected from the group consisting of

In certain embodiments of a compound of Formula (J) or (I), R⁴ is

In certain embodiments of a compound of Formula (J) or (I), R⁴ is

In certain embodiments of a compound of Formula (J) or (I), R⁴ is

In certain embodiments of a compound of Formula (J) or (I), R⁴ is

In certain embodiments of a compound of Formula (J) or (I), R⁴ is

In certain embodiments, the compound of Formula (J) or (I) is a compoundof Formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R⁵ is selected from the group consisting of hydrogen, halogen,        and methyl;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        and methyl; or R⁵ and R⁶ together form an oxo group;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        OR^(a) and NR^(a)R^(b);    -   R⁸ is selected from the group consisting of hydrogen and methyl;    -   R⁹ is selected from the group consisting of C₁₋₄ alkyl,        C₃₋₅cycloalkyl, and —S—C₁₋₄alkyl;    -   R^(a) and R^(b) are independently selected from the group        consisting of hydrogen and C₁₋₆alkyl; wherein each C₁₋₆alkyl is        optionally substituted with 1 to 3 substituents independently        selected from the group consisting of halogen, hydroxyl, and        pyridyl; and R¹, R², and R³ are as otherwise defined herein.

For example, in Formula (II), (IIa), and (IIb), R¹ is selected from thegroup consisting of hydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b),—S(O)₁₋₂R^(a), and OR^(a), wherein C₁₋₆alkyl is optionally substitutedwith 1 to 5 R²⁰ groups; R² is selected from the group consisting ofhydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) andOR^(a), wherein C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰groups; and R³ is selected from the group consisting of hydrogen,halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), whereinC₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;

In certain embodiments, the compound of Formula (II) is a compound ofFormula (IIa)

In certain embodiments, the compound of Formula (II) is a compound ofFormula (IIb)

In certain embodiments of the compound of Formula (II), (IIa), or (IIb),R⁵ is hydrogen; R⁶ is hydrogen; or R⁵ and R⁶ together form an oxo group;R⁷ is OR^(a) or NR^(a)R^(b); R⁸ is hydrogen; R⁹ is C₁₋₄ alkyl,cyclopropyl or —SCH₃; R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and C₁₋₄alkyl; wherein each C₁₋₄alkylis optionally substituted with 1 to 3 substituents independentlyselected from halogen, hydroxyl, pyrid-2-yl, and CF₃, and R¹, R², and R³are as otherwise defined herein. In certain embodiments, R^(a) and R^(b)are hydrogen. In certain embodiments, R⁷ is OH or NH₂. In certainembodiments, R¹ and R² are hydrogen.

In certain embodiments of a compound of Formula (IIa),

is selected from

In certain embodiments of a compound of Formula (IIa),

is selected from

In certain embodiments of a compound of formula (IIb),

is selected from

In certain embodiments of a compound of formula (IIb),

is selected from

In certain embodiments of the compound of Formula (II), (IIa), or (IIb),R⁵ is hydrogen, R⁶ is hydrogen, or R⁵ and R⁶ together form an oxo group,R⁷ is OR^(a) or NR^(a)R^(b), R⁸ is hydrogen, R⁹ is C₁₋₄alkyl,cyclopropyl or —SCH3, and R^(a) and R^(b) are independently selectedfrom the group consisting of hydrogen and C₁₋₄alkyl; wherein eachC₁₋₄alkyl is optionally substituted with 1 to 3 substituentsindependently selected from halogen, hydroxyl, pyrid-2-yl, and CF₃. Incertain embodiments of the compound of Formula (II), (IIa), or (IIb), R⁷is OH or NH₂.

In certain embodiments of a compound of Formula (J), Formula (I), orFormula (II), the compound is a compound of Formula (III)

wherein

-   -   R⁵ is hydrogen;    -   R⁶ is hydrogen; or R⁵ and R⁶ together form an oxo group;    -   R⁷ is selected from the group consisting of OR^(a) and        NR^(a)R^(b);    -   R^(a) and R^(b) are independently selected from the group        consisting of hydrogen and C₁₋₃alkyl; wherein each C₁₋₃alkyl is        optionally substituted with 1 to 3 substituents independently        selected from the group consisting of halogen and hydroxyl and        R¹, R², and R³ are as otherwise defined herein.

In certain embodiments the compound of Formula (III) is a compound ofFormula (IIIa)

In certain embodiments the compound of Formula (III) is a compound ofFormula (IIIb)

In certain embodiments of the compound of Formula (III), (IIIa), or(IIIb), R⁵ and R⁶ are both hydrogen and R⁷ is OR^(a), wherein R^(a) ishydrogen or C₁₋₃alkyl. In certain embodiments of the compound of Formula(III), (IIIa), or (IIIb), R⁵ and R⁶ are both hydrogen and R⁷ is OH. Incertain embodiments of the compound of Formula (III), (IIIa), or (IIIb),R¹, R², R⁵, and R⁶ are each hydrogen, and R⁷ is OH.

In certain embodiments of the compound of Formula (III), (IIIa), or(IIIb), R⁵ and R⁶ together form an oxo group and R⁷ is selected from thegroup consisting of OR^(a) and NR^(a)R^(b), wherein R^(a) and R^(b) areindependently selected from the group consisting of hydrogen andC₁₋₃alkyl. In certain embodiments of the compound of Formula (III),(IIIa), or (IIIb), R⁵ and R⁶ together form an oxo group and R⁷ isselected from the group consisting of OR^(a) and NR^(a)R^(b), whereinR^(a) and R^(b) are independently selected from the group consisting ofhydrogen and methyl.

In certain embodiments of a compound of Formula (J), or Formula (I), thecompound is a compound of Formula (IV):

The R¹, R², and R³ groups of Formula (IV) are as defined above forFormula (J) or (I). The R¹¹, R¹² and R¹³ groups are as defined above forR⁴ in Formula (J) or Formula (I).

In certain embodiments, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, is a compound of Formula(IVa):

In certain embodiments, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, is a compound of Formula(IVb):

The groups R¹, R², R³, R¹¹, R¹² and R¹³ of Formula (IVa) and (IVb) areas defined for Formula (J), (I) or (IV) above, or as defined below, orany combination thereof.

R¹ of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom hydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), andOR^(a), wherein C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰groups. In certain embodiments, R¹ is selected from hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally substitutedwith 1 to 5 R²⁰ groups. In certain embodiments, R¹ can be hydrogen,halogen, and C₁₋₃ alkyl, wherein C₁₋₃ alkyl is optionally substitutedwith 1 to 5 halogen groups. In certain embodiments, R¹ can be hydrogen,fluoro, chloro, bromo, methyl or ethyl, wherein each methyl or ethylgroup is optionally substituted with 1 to 5 halogen groups. In certainembodiments, R¹ can be hydrogen, fluoro, chloro, bromo, methyl or ethyl,wherein each methyl or ethyl group is optionally substituted with 1 to 5fluoro groups. In certain embodiments, R¹ can be hydrogen, methyl,fluoro, chloro, and CF₃. In certain embodiments, R¹ can be hydrogen. Incertain embodiments, R¹ is selected from hydrogen, halogen, NH₂, C₁₋₆alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally substituted with1 to 5 R²⁰ groups.

R² of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom hydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) andOR^(a), wherein C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰groups. In certain embodiments, R² is selected from hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl optionally substitutedwith 1 to 5 R²⁰ groups. In certain embodiments, R² is selected fromhydrogen, halogen, C₁₋₃ alkyl, CN and OR^(a), wherein C₁₋₃ alkyl isoptionally substituted with 1 to 5 halogen groups. In certainembodiments, R² is selected from hydrogen, methyl, ethyl, fluoro,chloro, bromo, CF₃, CN, OH, OMe, and OEt. In certain embodiments, R² isselected from hydrogen, methyl, fluoro, and chloro. In certainembodiments, R² is selected from hydrogen and fluoro. In certainembodiments, R² is selected from hydrogen, halogen, NH₂, C₁₋₆ alkyl, CN,and OR^(a), wherein C₁₋₆ alkyl is optionally substituted with 1 to 5 R²⁰groups. In certain embodiments, R² is selected from hydrogen, methyl,ethyl, NH₂, fluoro, chloro, bromo, CF₃, CN, OH, OMe, and OEt.

R³ of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom hydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), andOR^(a), wherein C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰groups. In certain embodiments, R³ is selected from hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally substitutedwith 1 to 5 R²⁰ groups. In certain embodiments, R³ can be selected fromhydrogen, halogen, and C₁₋₃ alkyl. In certain embodiments, R³ can beselected from hydrogen, methyl, fluoro, and chloro. In certainembodiments, R³ can be selected from hydrogen and methyl. In certainembodiments, R³ is selected from hydrogen, halogen, NH₂, C₁₋₆ alkyl, CN,and OR^(a), wherein C₁₋₆ alkyl is optionally substituted with 1 to 5 R²⁰groups.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is selected from the group consisting of hydrogen, halogen, C₁₋₆alkyl,CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein C₁₋₆alkyl isoptionally substituted with 1 to 5 R²⁰ groups, R² is selected from thegroup consisting of hydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b),—S(O)₁₋₂R^(a) and OR^(a), wherein C₁₋₆alkyl is optionally substitutedwith 1 to 5 R²⁰ groups, and R³ is selected from the group consisting ofhydrogen, halogen, C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), andOR^(a), wherein C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰groups.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is selected from the group consisting of hydrogen, halogen, and C₁₋₃alkyl, wherein C₁₋₃ alkyl is optionally substituted with 1 to 5 halogengroups, R² is selected from the group consisting of hydrogen, halogen,C₁₋₃ alkyl, CN and OR^(a), wherein C₁₋₃ alkyl is optionally substitutedwith 1 to 5 halogen groups, and R³ is selected from the group consistingof hydrogen, halogen, and C₁₋₃ alkyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is selected from the group consisting of hydrogen, methyl, fluoro,chloro, and CF₃, R² is selected from the group consisting of hydrogen,methyl, ethyl, fluoro, chloro, bromo, CF₃, CN, OH, OMe, and OEt, and R³is selected from the group consisting of hydrogen, methyl, fluoro, andchloro.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is selected from the group consisting of hydrogen, methyl, fluoro,chloro, and CF₃, R² is selected from the group consisting of hydrogen,methyl, ethyl, NH₂, fluoro, chloro, bromo, CF₃, CN, OH, OMe, and OEt,and R³ is selected from the group consisting of hydrogen, methyl,fluoro, and chloro.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is hydrogen, R² is selected from the group consisting of hydrogen,methyl, ethyl, fluoro, chloro, and bromo, and R³ is selected from thegroup consisting of hydrogen and methyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹is hydrogen. R² is selected from the group consisting of hydrogen andfluoro, and R³ is selected from the group consisting of hydrogen andmethyl.

In certain embodiments, R¹¹ of Formula (IV), (IVa) and (IVb) can be anysuitable group selected from hydrogen, C₁₋₂ alkyl, C₃₋₆ cycloalkyl, andC₁₋₃ haloalkyl. In certain embodiments, the compound of Formula (IV),(IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is thecompound wherein R¹¹ is selected from the group consisting of hydrogen,C₁₋₂ alkyl and C₁₋₂ haloalkyl. In certain embodiments, the compound ofFormula (IV), (IVa) or (IVb), or a pharmaceutically acceptable saltthereof, is the compound wherein R¹¹ is selected from the groupconsisting of C₁₋₂ alkyl and C₁₋₂ haloalkyl. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, is the compound wherein R¹¹ can be selectedfrom hydrogen, methyl, ethyl or CF₃. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, is the compound wherein R¹¹ can be selectedfrom methyl, ethyl or CF₃. In certain embodiments, the compound ofFormula (IV), (IVa) or (IVb), or a pharmaceutically acceptable saltthereof, is the compound wherein R¹¹ can be selected from hydrogen,methyl, or CF₃. In certain embodiments, the compound of Formula (IV),(IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is thecompound wherein R¹¹ can be selected from methyl, or CF₃. In certainembodiments, the compound of Formula (IV), (IVa) or (IVb), or apharmaceutically acceptable salt thereof, is the compound wherein R¹¹can be selected from hydrogen or methyl. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ is selected from the groupconsisting of methyl and CF₃. In certain embodiments, the compound ofFormula (IV), (IVa) or (IVb), or a pharmaceutically acceptable saltthereof, is the compound wherein R¹¹ is methyl. In certain embodiments,the compound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, is the compound wherein R¹¹ is hydrogen.

R¹² of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a),—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, C₆₋₁₀aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 memberedheteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, andsulfur, wherein the C₁₋₃ alkyl group is optionally substituted with 1 to5 substituents independently selected from halogen, —OR^(a),—NR^(a)R^(b), CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),—NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),—NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 memberedheterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, wherein R¹² can be selectedfrom C₁₋₂ alkyl, —C(O)NR^(a)R^(b), and 5 membered heteroaryl having 1 to3 nitrogen heteroatoms, wherein C₁₋₂ alkyl is optionally substitutedwith 1 to 5 substituents independently selected from halogen, —OH,—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)S(O)₂R^(b), and C₁₋₃ haloalkyl,and each R^(a) and R^(b) is independently selected from the groupconsisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom hydroxyl and amino. In certain embodiments, the compound of Formula(IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof,wherein R¹² is C₁₋₂ alkyl, optionally substituted with 1 to 3substituents independently selected from halogen, —OH, —NH₂,—NHC(O)—C₁₋₃ alkyl, —NHS(O)₂—C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In certainembodiments, the compound of Formula (IV), (IVa) or (IVb), or apharmaceutically acceptable salt thereof, wherein R¹² is methyl orethyl, each optionally substituted with 1 or 2 substituentsindependently selected from halogen, —OH, —NH₂, —NHC(O)—C₁₋₃ alkyl, andC₁₋₃ haloalkyl. In certain embodiments, the compound of Formula (IV),(IVa) or (IVb), or a pharmaceutically acceptable salt thereof, whereinR¹² is methyl or ethyl, wherein the methyl or ethyl is substituted with1 or 2 substituents independently selected from —OH and —NHC(O)CH₃. Incertain embodiments, the compound of Formula (IV), (IVa) or (IVb), or apharmaceutically acceptable salt thereof, wherein R¹² can be selectedfrom CH₂OH, CH₂CH₂OH, CH(Me)OH, CH(CH₂F)OH, CH(CHF₂)OH, CH(CF₃)OH, CF₃,CH₂NH₂, CH₂NHC(O)Me, CH(CH₂F)NHC(O)Me, CH₂NHS(O)₂Me, C(O)NH₂, C(O)NHMe,C(O)NH—CH₂CH₂OH, C(O)NH—CH₂CH₂NH₂, C(O)NH-(pyridin-2-ylmethyl),imidazolyl, and triazolyl. In certain embodiments, the compound ofFormula (IV), (IVa) or (IVb), or a pharmaceutically acceptable saltthereof, wherein R¹² can be selected from CH₂OH, CH(Me)OH, CH(CH₂F)OH,and CH₂NHC(O)Me. In certain embodiments, the compound of Formula (IV),(IVa) or (IVb), or a pharmaceutically acceptable salt thereof, whereinR¹² can be selected from CH₂OH, CH(Me)OH, and CH₂NHC(O)Me. In certainembodiments, the compound of Formula (IV), (IVa) or (IVb), or apharmaceutically acceptable salt thereof, wherein R¹² is —CH₂OH or—CH₂NC(O)CH₃.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₂ alkylsubstituted with —NR^(a)C(O)R^(b), wherein each R^(a) and R^(b) isindependently selected from the group consisting of hydrogen and C₁₋₃alkyl, wherein each C₁₋₃ alkyl is optionally substituted with 1 to 3substituents independently selected from hydroxyl and amino.

R¹³ of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a),—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, C₆₋₁₀aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 memberedheteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, andsulfur, wherein the C₁₋₆ alkyl is optionally substituted with 1 to 5substituents independently selected from halogen, —OR^(a), —NR^(a)R^(b),CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),—S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6membered heterocyclyl has 1 to 3 heteroatoms selected from oxygen,nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroarylwherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selectedfrom oxygen, nitrogen, and sulfur.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein R¹³is C₃₋₆ alkyl optionally substituted with 1 to 2 substituentsindependently selected from halogen and —OH. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, is the compound wherein R¹³ is C₃₋₆ alkyloptionally substituted with 1 to 2 halogen substituents. In certainembodiments, the compound of Formula (IV), (IVa) or (IVb), or apharmaceutically acceptable salt thereof, is the compound wherein R¹³ isC₃₋₆ alkyl. Representative C₃₋₆ alkyl groups for R¹³ include, but arenot limited to, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl and3-pentyl. In certain embodiments, the compound of Formula (IV), (IVa) or(IVb), or a pharmaceutically acceptable salt thereof, is the compoundwherein R¹³ is propyl, butyl or pentyl. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVb), or a pharmaceuticallyacceptable salt thereof, is the compound wherein R¹³ is n-propyl,n-butyl or n-pentyl. In certain embodiments, the compound of Formula(IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, isthe compound wherein R¹³ is propyl or butyl.

R²⁰ of Formula (IV), (IVa) and (IVb) can be any suitable group selectedfrom halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a), and OR^(a).In certain embodiments, each R²⁰ can independently be selected fromhalogen, CN, —NR^(a)R^(b), and OR^(a). In certain embodiments, each R²⁰can independently be selected from halogen, CN, —NR^(a)R^(b), andOR^(a). In certain embodiments, each R²⁰ can independently be halogen.In certain embodiments, each R²⁰ can independently be selected fromfluoro, chloro, bromo, CN, —NH₂, OH, OMe, and OEt. In certainembodiments, each R²⁰ can independently be selected from fluoro andchloro.

R^(a) and R^(b) of Formula (IV), (IVa) and (IVb) can each independentlybe any suitable group selected from the group consisting of hydrogen andC₁₋₆alkyl; wherein each C₁₋₆alkyl is optionally substituted with 1 to 5substituents independently selected from halogen, hydroxyl, amino, 5 to10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to3 heteroatoms selected from oxygen, nitrogen, and sulfur, andC₁₋₆haloalkyl. In certain embodiments, R^(a) and R^(b) can eachindependently be selected from hydrogen and C₁₋₃ alkyl, wherein eachC₁₋₃ alkyl is optionally substituted with 1 to 3 substituentsindependently selected from halogen, hydroxyl, amino, and C₁₋₆haloalkyl. In certain embodiments, R^(a) and R^(b) can eachindependently be selected from hydrogen and C₁₋₃ alkyl, wherein eachC₁₋₃ alkyl is optionally substituted with 1 to 3 substituentsindependently selected from hydroxyl and amino. In certain embodiments,R^(a) and R^(b) can each independently be selected from hydrogen andC₁₋₃ alkyl, wherein each C₁₋₃ alkyl is optionally substituted with 1substituent selected from hydroxyl and amino. In certain embodiments,R^(a) and R^(b) can each independently be selected from hydrogen andC₁₋₃ alkyl. In certain embodiments, R^(a) and R^(b) can eachindependently be selected from hydrogen, methyl, ethyl, propyl, butyl,CF₃, CH₂CF₃, CH₂CH₂CF₃, CH₂OH, CH₂CH₂OH, CH₂NH₂, and CH₂CH₂NH₂. Incertain embodiments, R^(a) and R^(b) can each independently be selectedfrom hydrogen, methyl, ethyl, CF₃, CH₂OH, CH₂CH₂OH, CH₂NH₂, andCH₂CH₂NH₂. In certain embodiments, R^(a) and R^(b) can eachindependently be selected from hydrogen, methyl, ethyl, CH₂CH₂OH, andCH₂CH₂NH₂. In certain embodiments, R^(a) and R^(b) can eachindependently be selected from hydrogen, methyl and ethyl. In certainembodiments, R^(a) and R^(b) can each independently be selected fromhydrogen and methyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R¹¹ is selected from the group consisting of hydrogen, C₁₋₂        alkyl, C₃₋₆ cycloalkyl, and C₁₋₃ haloalkyl;    -   R¹² is selected from C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₃ alkyl group is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   R¹³ is selected from C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₆ alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   each R²⁰ is independently selected from the group consisting of        halogen, CN, —NR^(a)R^(b), and OR^(a); and    -   each R^(a) and R^(b) is independently selected from the group        consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl        is optionally substituted with 1 to 3 substituents independently        selected from halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a) and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆alkyl, CN, —NR^(a)R^(b), —S(O)₁₋₂R^(a), and OR^(a), wherein        C₁₋₆alkyl is optionally substituted with 1 to 5 R²⁰ groups;    -   R¹¹ is selected from the group consisting of C₁₋₂ alkyl, C₃₋₆        cycloalkyl, and C₁₋₃ haloalkyl;    -   R¹² is selected from C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₃ alkyl group is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   R¹³ is selected from C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₆ alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   each R²⁰ is independently selected from the group consisting of        halogen, CN, —NR^(a)R^(b), and OR^(a); and    -   each R^(a) and R^(b) is independently selected from the group        consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl        is optionally substituted with 1 to 3 substituents independently        selected from halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl optionally        substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R¹¹ is selected from the group consisting of hydrogen, C₁₋₂        alkyl, C₃₋₆ cycloalkyl, and C₁₋₃ haloalkyl;    -   R¹² is selected from C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₃ alkyl group is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   R¹³ is selected from C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₆ alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   each R²⁰ is independently selected from the group consisting of        halogen, CN, —NR^(a)R^(b), and OR^(a); and    -   each R^(a) and R^(b) is independently selected from the group        consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl        is optionally substituted with 1 to 3 substituents independently        selected from halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, is the compound wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R² is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl optionally        substituted with 1 to 5 R²⁰ groups;    -   R³ is selected from the group consisting of hydrogen, halogen,        C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally        substituted with 1 to 5 R²⁰ groups;    -   R¹¹ is selected from the group consisting of C₁₋₂ alkyl, C₃₋₆        cycloalkyl, and C₁₋₃ haloalkyl;    -   R¹² is selected from C₁₋₃ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₃ alkyl group is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₃        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   R¹³ is selected from C₁₋₆ alkyl, halogen, —OR^(a), —NR^(a)R^(b),        CN, —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),        —OC(O)NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b),        —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂NR^(a)R^(b),        —NR^(a)S(O)₂R^(b), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 3 to 6        membered heterocyclyl wherein the 3 to 6 membered heterocyclyl        has 1 to 3 heteroatoms selected from oxygen, nitrogen, and        sulfur, C₆₋₁₀ aryl, and 5 to 10 membered heteroaryl wherein the        5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur, wherein the C₁₋₆ alkyl is        optionally substituted with 1 to 5 substituents independently        selected from halogen, —OR^(a), —NR^(a)R^(b), CN, —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(b), —NR^(a)C(O)OR^(b), —SR^(a),        —S(O)₁₂R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 3 to 6 membered heterocyclyl wherein        the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected        from oxygen, nitrogen, and sulfur, C₆₋₁₀ aryl, and 5 to 10        membered heteroaryl wherein the 5 to 10 membered heteroaryl has        1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;    -   each R²⁰ is independently selected from the group consisting of        halogen, CN, —NR^(a)R^(b), and OR^(a); and    -   each R^(a) and R^(b) is independently selected from the group        consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl        is optionally substituted with 1 to 3 substituents independently        selected from halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is methyl orCF₃, R¹² is —CH₂OH, —CH(Me)OH or —CH₂NHC(O)CH₃, and R¹³ is selected fromthe group consisting of propyl, butyl and pentyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is methyl orCF₃, R¹² is —CH₂OH, —CH(Me)OH, CH₂NHCH(CH₃)(CF₃) or —CH₂NHC(O)CH₃, andR¹³ is selected from the group consisting of propyl, butyl and pentyl.

In certain embodiments, the compound of Formula (IV), (IVa) or (IVb), ora pharmaceutically acceptable salt thereof, wherein R¹¹ is methyl, R¹²is —CH₂OH or —CH₂NHC(O)CH₃, and R¹³ is selected from the groupconsisting of propyl and butyl.

In certain embodiments, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, wherein the moiety is

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, wherein the moiety

can also be drawn as the moiety

In certain embodiments, the compound of Formula (IV) or (IVb), or apharmaceutically acceptable salt thereof, wherein the moiety

is

In certain embodiments, the compound of Formula (IV) or (IVb), or apharmaceutically acceptable salt thereof, wherein the moiety

can also be drawn as the moiety

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, is a compound of Formula (IVc)

The R², R¹² and R¹³ groups of Formula (IVc) are as defined above forFormula (J), (I), (IV) or (IVa), or any combination thereof. Forexample, R² can be selected from hydrogen, halogen, C₁₋₃ alkyl, CN andOR^(a), wherein C₁₋₃ alkyl is optionally substituted with 1 to 5 halogengroups, R¹² can be selected from C₁₋₂ alkyl, —C(O)NR^(a)R^(b), and 5membered heteroaryl having 1 to 3 nitrogen heteroatoms, wherein C₁₋₂alkyl is optionally substituted with 1 to 5 substituents independentlyselected from halogen, —OH, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)S(O)₂R^(b), and C₁₋₃ haloalkyl, and R¹³ can be C₃₋₆ alkyloptionally substituted with 1 to 2 substituents independently selectedfrom halogen and —OH. In certain embodiments, the compound of Formula(IV), (IVa), or (IVc), or a pharmaceutically acceptable salt thereof, isa compound wherein R² can be selected from hydrogen, methyl, ethyl,fluoro, chloro, bromo, CF₃, CN, OH, OMe, and OEt, and R¹² can beselected CH₂OH, CH₂CH₂OH, CH(Me)OH, CH(CH₂F)OH, CH(CHF₂)OH, CH(CF₃)OH,CF₃, CH₂NH₂, CH₂NHC(O)Me, CH(CH₂F)NHC(O)Me, CH₂NHS(O)₂Me, C(O)NH₂,C(O)NHMe, C(O)NH—CH₂CH₂OH, C(O)NH—CH₂CH₂NH₂,C(O)NH-(pyridin-2-ylmethyl), imidazolyl, and triazolyl, and R¹³ can bepropyl, butyl or pentyl. In certain embodiments, the compound of Formula(IV), (IVa), or (IVc), or a pharmaceutically acceptable salt thereof, isa compound wherein R² can be selected from hydrogen, methyl, fluoro, andchloro, and R¹² can be selected CH₂OH, CH(Me)OH, CH(CH₂F)OH, andCH₂NHC(O)Me, and R¹³ can be propyl, butyl or pentyl. In certainembodiments, the compound of Formula (IV), (IVa), or (IVc), or apharmaceutically acceptable salt thereof, is a compound wherein R² ishydrogen or fluoro, R¹² is —CH₂OH or —CH₂NHC(O)CH₃, and R¹³ is selectedfrom propyl and butyl. In certain embodiments, the compound of Formula(IV), (IVa), or (IVc), or a pharmaceutically acceptable salt thereof, isa compound wherein R² is hydrogen, chloro, or fluoro, R¹² is —CH₂OH or—CH₂NHC(O)CH₃, and R¹³ is selected from butyl or pentyl.

In certain embodiments, the compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt thereof, is a compound of Formula (IVd)

The R¹, R², R³, R¹¹, R¹³, R^(a) and R^(b) groups of Formula (IVd) can beas defined above for Formula (J), (I), (IV), or (IVa), or anycombination thereof. R^(12a) can be any suitable group selected fromhydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVd), or a pharmaceuticallyacceptable salt thereof, is a compound wherein R^(12a) can be selectedfrom hydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl. In certain embodiments,the compound of Formula (IV), (IVa) or (IVd), or a pharmaceuticallyacceptable salt thereof, is a compound wherein R^(12a) can be selectedfrom hydrogen, methyl, ethyl and CF₃. In certain embodiments, thecompound of Formula (IV), (IVa) or (IVd), or a pharmaceuticallyacceptable salt thereof, is a compound wherein R^(12a) can be hydrogen.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, is the compound wherein R¹ isselected from the group consisting of hydrogen, halogen, C₁₋₆ alkyl, CN,and OR^(a), wherein C₁₋₆ alkyl is optionally substituted with 1 to 5 R²⁰groups, R² is selected from the group consisting of hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl optionally substitutedwith 1 to 5 R²⁰ groups, R³ is selected from the group consisting ofhydrogen, halogen, C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl isoptionally substituted with 1 to 5 R²⁰ groups, R¹¹ is C₁₋₂ alkyl or CF₃,R^(12a) is selected from the group consisting of hydrogen, C₁₋₂ alkyland C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyl optionally substituted with 1 to 2halogen substituents, each R²⁰ is independently selected from the groupconsisting of halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a),and OR^(a), and each R^(a) and R^(b) is independently selected from thegroup consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, is the compound wherein R¹ isselected from the group consisting of hydrogen, halogen, and C₁₋₃ alkyl,R² is selected from the group consisting of hydrogen, halogen, and C₁₋₃alkyl, R³ is selected from the group consisting of hydrogen, halogen,and C₁₋₃ alkyl, R¹¹ is C₁₋₂ alkyl or CF₃, R^(12a) is selected from thegroup consisting of hydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl, R¹³ is C₃₋₆alkyl optionally substituted with 1 to 2 halogen substituents, and eachR^(a) and R^(b) is independently selected from the group consisting ofhydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl is optionallysubstituted with 1 to 3 substituents independently selected fromhalogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R² is selected from the group consisting of hydrogen, methyl,fluoro, and chloro, R³ is selected from the group consisting of hydrogenand methyl, R^(12a) is selected from the group consisting of hydrogen,C₁₋₂ alkyl and C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyl, and R^(b) is methyl orethyl, each optionally substituted with hydroxyl or amino.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R² is selected from the group consisting of hydrogen, methyl,fluoro, and chloro, R^(12a) is selected from the group consisting ofhydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyl, and R^(b) ismethyl or ethyl, each optionally substituted with hydroxyl or amino. Incertain embodiments, R² and R¹³ can be as defined above for Formula (J),(I), (IV), or (IVa), or any combination thereof.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R³ is selected from the group consisting of hydrogen and methyl,R^(12a) is selected from the group consisting of hydrogen, C₁₋₂ alkyland C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyl, and R^(b) is methyl or ethyl,each optionally substituted with hydroxyl or amino.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R¹³ is C₃₋₆ alkyl. R¹, R² and R³ can be as defined above forFormula (J), (I), (IV), (IVa) or (IVd).

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R² is selected from the group consisting of hydrogen and F, andR¹³ is C₃₋₆ alkyl. In certain embodiments, R² and R¹³ can be as definedabove for Formula (J), (I), (IV), or (IVa), or any combination thereof.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R² is selected from the group consisting of hydrogen, Cl, and F,and R¹³ is C₃₋₆ alkyl. In certain embodiments, R² and R¹³ can be asdefined above for Formula (J), (I), (IV), or (IVa), or any combinationthereof.

In certain embodiments, the compound of Formula (IVd), or apharmaceutically acceptable salt thereof, has the structure:

wherein R³ is selected from the group consisting of hydrogen and methyl,and R¹³ is C₃₋₆ alkyl.

In certain embodiments, the compound of Formula (J), (I), or (IV), isselected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), or (IV), isselected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), or (IV), or apharmaceutically acceptable salt thereof, is a compound of the followingformula:

wherein R¹ is selected from the group consisting of hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally substitutedwith 1 to 5 R²⁰ groups, R² is selected from the group consisting ofhydrogen, halogen, C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyloptionally substituted with 1 to 5 R²⁰ groups, R³ is selected from thegroup consisting of hydrogen, halogen, C₁₋₆ alkyl, CN, and OR^(a),wherein C₁₋₆ alkyl is optionally substituted with 1 to 5 R²⁰ groups,R^(12a) is selected from the group consisting of hydrogen, C₁₋₂ alkyland C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyl optionally substituted with 1 to 2halogen substituents, each R²⁰ is independently selected from the groupconsisting of halogen, C₁₋₆haloalkyl, CN, —NR^(a)R^(b), S(O)₁₋₂R^(a),and OR^(a), and each R^(a) and R^(b) is independently selected from thegroup consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (J), (I), or (IV), or apharmaceutically acceptable salt thereof, is a compound of the followingformula:

wherein R¹ is selected from the group consisting of hydrogen, halogen,and C₁₋₃ alkyl, R² is selected from the group consisting of hydrogen,halogen, and C₁₋₃ alkyl, R³ is selected from the group consisting ofhydrogen, halogen, and C₁₋₃ alkyl, R^(12a) is selected from the groupconsisting of hydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl, R¹³ is C₃₋₆ alkyloptionally substituted with 1 to 2 halogen substituents, and each R^(a)and R^(b) is independently selected from the group consisting ofhydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl is optionallysubstituted with 1 to 3 substituents independently selected fromhalogen, hydroxyl, amino, and C₁₋₆ haloalkyl.

In certain embodiments, the compound of Formula (J), (I), or (IV), or apharmaceutically acceptable salt thereof, is a compound of the followingformula:

wherein R¹³ is C₃₋₆ alkyl. R¹, R² and R³ can be as defined above forFormula (J), (I), (IV), (IVa) or (IVd).

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R¹ is hydrogen, halogen, or C₁₋₆alkyloptionally substituted with 1 to 5 R²⁰ groups. In certain embodiments ofa compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IV), (IVa), (IVb), or (IVd), R¹ is hydrogen, halogen, orC₁₋₆alkyl optionally substituted with 1 to 5 R²⁰ groups.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R¹ is hydrogen, halogen, or C₁₋₃alkyloptionally substituted with 1 to 5 halogens. In certain embodiments of acompound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb),(IV), (IVa), (IVb) or (IVd), R¹ is hydrogen, halogen, or C₁₋₃alkyloptionally substituted with 1 to 5 halogens.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R¹ is hydrogen, Cl, CH₃, or CF₃. Incertain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb) or (IVd), R¹ ishydrogen, Cl, CH₃, or CF₃.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R² is hydrogen, halogen, CN, orC₁₋₆alkyl optionally substituted with 1 to 5 R²⁰ groups. In certainembodiments of a compound of Formula (J), (I), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd), R² ishydrogen, halogen, CN, or C₁₋₆alkyl optionally substituted with 1 to 5R²⁰ groups.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R² is hydrogen, halogen, CN orC₁₋₃alkyl optionally substituted with 1 to 5 halogens. In certainembodiments of a compound of Formula (J), (I), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd), R² ishydrogen, halogen, CN or C₁₋₃alkyl optionally substituted with 1 to 5halogens.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R² is hydrogen, CH₃, —CH₂CH₃, F, Br,Cl, or CN. In certain embodiments of a compound of Formula (J), (I),(II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or(IVd), R² is hydrogen, CH₃, —CH₂CH₃, F, Br, Cl, or CN.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R³ is hydrogen, halogen, or C₁₋₆alkyloptionally substituted with 1 to 5 R²⁰ groups. In certain embodiments ofa compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IV), (IVa), (IVb) or (IVd), R³ is hydrogen, halogen, orC₁₋₆alkyl optionally substituted with 1 to 5 R²⁰ groups.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R³ is hydrogen, halogen, or C₁₋₃alkyloptionally substituted with 1 to 5 R²⁰ groups. In certain embodiments ofa compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IV), (IVa), (IVb) or (IVd), R³ is hydrogen, halogen, orC₁₋₃alkyl optionally substituted with 1 to 5 R²⁰ groups.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R³ is hydrogen, Cl, or CH₃. In certainembodiments of a compound of Formula (J), (I), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb) or (IVd), R³ is hydrogen, Cl,or CH₃.

In certain embodiments of a compound of Formula (J), R¹⁰ is hydrogen, F,Cl, or CH₃.

In certain embodiments of a compound of Formula (J), R¹⁰ is hydrogen.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R¹, R², and R³ are hydrogen. In certainembodiments of a compound of Formula (J), (I), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb), ((IVc), or (IVd), R¹, R², andR³ are hydrogen.

In certain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), or (IIIb), R¹ and R³ are hydrogen and R² is F. Incertain embodiments of a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd), R¹and R³ are hydrogen and R² is F.

It is understood that each of the variables (e.g. R¹, R², R³, R⁴) may becombined with any other variables for Formula (J), (I), (II), (IIa) or(IIb) (e.g. R¹, R², R³, R⁴). Further, in instances describing a compoundof Formula (J) or (I), it is understood that the variables also describecompounds of other formulae (e.g. Formula (II), (IIa), (IIb), (III),(IIIa), and (IIIb)) which fall within the scope of Formula (J) or (I).

It is understood that any variable for R¹ of Formula (J), (I), (II),(IIa), (IIb), (III), (IIIa), or (IIIb) may be combined with any variableof R⁴ in Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb),the same as if each and every combination were specifically andindividually listed. For example, in one variation of Formula (J) or(I), R¹ is hydrogen, Cl, CH₃ or CF₃, and R⁴ is C₁₋₆ alkyl which isoptionally substituted with 1 or 2 substituents independently selectedfrom OH, CF₃, —C(O)OH, —C(O)OCH₃, —C(O)NH₂, SCH₃, —C(O)NHCH₃,—C(O)NHCH₂CH₂NH₂, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂-pyridyl, phenyl,tetrahydrofuranyl, and cyclopropyl

It is understood that any variable for R² of Formula (J), (I), (II),(IIa), (IIb), (III), (IIIa), or (IIIb) may be combined with any variableof R⁴ in Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb),the same as if each and every combination were specifically andindividually listed. For example, in one variation of Formula (J) or(I), R² is hydrogen, CH₃, —CH₂CH₃, F, Br, Cl, or CN, and R⁴ is C₁₋₆alkyl which is optionally substituted with 1 or 2 substituentsindependently selected from OH, CF₃, —C(O)OH, —C(O)OCH₃, —C(O)NH₂, SCH₃,—C(O)NHCH₃, —C(O)NHCH₂CH₂NH₂, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂-pyridyl,phenyl, tetrahydrofuranyl, and cyclopropyl.

It is understood that any variable for R³ of Formula (J), (I), (II),(IIa), (IIb), (III), (IIIa), or (IIIb) may be combined with any variableof R⁴ in Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb),the same as if each and every combination were specifically andindividually listed. For example, in one variation of Formula (J) or(I), R³ is hydrogen, Cl, or CH₃, and R⁴ is C₁₋₆ alkyl which isoptionally substituted with 1 or 2 substituents independently selectedfrom OH, CF₃, —C(O)OH, —C(O)OCH₃, —C(O)NH₂, SCH₃, —C(O)NHCH₃,—C(O)NHCH₂CH₂NH₂, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂-pyridyl, phenyl,tetrahydrofuranyl, and cyclopropyl.

In certain embodiments, the compound of Formula (J) or (I), or apharmaceutically acceptable salt thereof, has one or more featuresselected from:

-   -   (a) R⁴ is C₁₋₆ alkyl which is optionally substituted with 1 or 2        substituents independently selected halogen, —OR^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —SR^(a), C₁₋₃haloalkyl,        C₃₋₆cycloalkyl, 3 to 6 membered heterocyclyl and C₆₋₁₀ aryl;        wherein each C₃₋₆cycloalkyl and C₆₋₁₀ aryl is optionally        substituted with 1 to 3 R²¹ groups and wherein R^(a) and R^(b)        are each independently hydrogen or C₁₋₄alkyl, wherein each C₁₋₄        alkyl is optionally substituted with —NH₂, OH, or pyridyl;    -   (b) R¹ is hydrogen, halogen, or C₁₋₆alkyl optionally substituted        with 1 to 5 R²⁰ groups;    -   (c) R² is hydrogen, halogen, CN, or C₁₋₆alkyl optionally        substituted with 1 to 5 R²⁰ groups; and    -   (d) R³ is hydrogen, halogen, or C₁₋₃alkyl optionally substituted        with 1 to 5 R²⁰ groups.        In certain embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has two or more        features selected from (a)-(d), as listed above. In certain        embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has three or more        features selected from (a)-(d), as listed above. In certain        embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has four features        selected from (a)-(d), as listed above.

In certain embodiments, the compound of Formula (J) or (I), or apharmaceutically acceptable salt thereof has one or more featuresselected from:

-   -   (e) R⁴ is C₁₋₆ alkyl which is optionally substituted with 1 or 2        substituents independently selected from OH, CF₃, —C(O)OH,        —C(O)OCH₃, —C(O)NH₂, SCH₃, —C(O)NHCH₃, —C(O)NHCH₂CH₂NH₂,        —C(O)NHCH₂CH₂OH, —C(O)NHCH₂-pyridyl, phenyl, tetrahydrofuranyl,        and cyclopropyl.    -   (f) R¹ is hydrogen, halogen, or C₁₋₃alkyl optionally substituted        with 1 to 5 halogens;    -   (g) R² is hydrogen, halogen, CN or C₁₋₃alkyl optionally        substituted with 1 to 5 halogens; and    -   (h) R³ is hydrogen, halogen, or C₁₋₃alkyl.        In certain embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has two or more        features selected from (e)-(h), as listed above. In certain        embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has three or more        features selected from (e)-(h), as listed above. In certain        embodiments, the compound of Formula (J) or (I), or a        pharmaceutically acceptable salt thereof has two or more        features selected from (e)-(h), as listed above.

In certain embodiments, the compound of Formula (J) or (I) is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J) or (I) is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J) or (I) is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J) is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J) or (I) is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa)is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa)is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa)is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa)is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (J), (I), (IV), or (IVa)is selected from:

or a pharmaceutically acceptable salt thereof.

As used herein, “a compound of Formula (I)” includes compounds forFormula (II) (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb),(IVc), or (IVd).

III. COMPOSITIONS

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure (e.g.

a compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IV), (IVa), (IVb), (IVc), or (IVd)), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the pharmaceutical composition comprises one ormore additional therapeutic agent, as more fully set forth below.

Pharmaceutical compositions comprising the compounds disclosed herein,or pharmaceutically acceptable salts thereof, may be prepared with oneor more pharmaceutically acceptable excipients which may be selected inaccord with ordinary practice. Tablets may contain excipients includingglidants, fillers, binders and the like. Aqueous compositions may beprepared in sterile form, and when intended for delivery by other thanoral administration generally may be isotonic. All compositions mayoptionally contain excipients such as those set forth in the Rowe et al,Handbook of Pharmaceutical Excipients, 6^(th) edition, AmericanPharmacists Association, 2009. Excipients can include ascorbic acid andother antioxidants, chelating agents such as EDTA, carbohydrates such asdextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearicacid and the like. In certain embodiments, the composition is providedas a solid dosage form, including a solid oral dosage form.

The compositions include those suitable for various administrationroutes, including oral administration. The compositions may be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient (e.g., a compound of the presentdisclosure or a pharmaceutical salt thereof) with one or morepharmaceutically acceptable excipients. The compositions may be preparedby uniformly and intimately bringing into association the activeingredient with liquid excipients or finely divided solid excipients orboth, and then, if necessary, shaping the product. Techniques andformulations generally are found in Remington: The Science and Practiceof Pharmacy, 21^(st) Edition, Lippincott Williams and Wilkins,Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient. In one embodiment, thepharmaceutical composition is a tablet.

Pharmaceutical compositions disclosed herein comprise one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable excipient andoptionally other therapeutic agents. Pharmaceutical compositionscontaining the active ingredient may be in any form suitable for theintended method of administration. When used for oral use for example,tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, syrups or elixirsmay be prepared. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore excipients including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,lactose monohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutically acceptable excipient varies from about 5 to about 95%of the total compositions (weight:weight).

In certain embodiments, a composition comprising a compound of thepresent disclosure (e.g. a compound of Formula (J), (I), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd)), or apharmaceutically acceptable salt thereof in one variation does notcontain an agent that affects the rate at which the active ingredient ismetabolized. Thus, it is understood that compositions comprising acompound of the present disclosure in one aspect do not comprise anagent that would affect (e.g., slow, hinder or retard) the metabolism ofa compound of the present disclosure or any other active ingredientadministered separately, sequentially or simultaneously with a compoundof the present disclosure. It is also understood that any of themethods, kits, articles of manufacture and the like detailed herein inone aspect do not comprise an agent that would affect (e.g., slow,hinder or retard) the metabolism of a compound of the present disclosureor any other active ingredient administered separately, sequentially orsimultaneously with a compound of the present disclosure.

IV. METHODS

The present disclosure provides for methods of treating diseases orconditions that are responsive to the modulation of toll-like receptors(e.g. TLR-8 receptors). While not wishing to be bound by any one theory,the presently disclosed compounds are believed to modulate TLR-8receptors as agonists. As is understood by those of skill in the art,modulators of TLR-8 may, to some degree, modulate other toll-likereceptors (e.g. TLR-7). As such, in certain embodiments, the compoundsdisclosed herein may also modulate TLR-7 to a measureable degree. Incertain embodiments, those compounds that modulate TLR-8 to a higherdegree than TLR-7 are considered selective modulators of TLR-8.Exemplary methods of measuring the each compounds respective modulationof TLR-7 and TLR-8 are described in the Examples provided herein. Incertain embodiments, the compounds disclosed herein are selectivemodulators of TLR-8.

In certain embodiments, a method of modulating TLR-8 is provided,comprising administering a compound of the present disclosure, or apharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, a method of modulating TLR-8 in vitro isprovided.

In certain embodiments, the present disclosure provides a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,for use as a research tool, e.g., for use in identifying modulators ofTLR-8

In certain embodiments, the present disclosure provides methods for thetreatment or prevention of diseases or conditions in an individual (e.g.a human) in need thereof, comprising administering a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof. Incertain embodiments, the methods comprise administering one or moreadditional therapeutic agents. Treatment with a compound of the presentdisclosure typically results in the stimulation of an immune response tothe particular disease or condition being treated. Diseases orconditions contemplated by the present disclosure include those affectedby the modulation of toll-like receptors (e.g. TLR-8). In certainembodiments, a method of treating or preventing a disease or conditionresponsive to the modulation of TLR-8 is provided, comprisingadministering to a human a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof. Exemplary diseases, disorders and conditions include butare not limited to conditions involving autoimmunity, inflammation,allergy, asthma, graft rejection, graft versus host disease (GvHD),infectious diseases, cancer, and immunodeficiency.

In certain embodiments, infectious diseases include diseases such ashepatitis A, hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV),HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV),severe acute respiratory syndrome (SARS), influenza, parainfluenza,cytomegalovirus, dengue, herpes simplex virus-1, herpes simplex virus-2,leishmania infection, and respiratory syncytial virus. In certainembodiments, infectious diseases include diseases such as hepatitis A,hepatitis B (HBV), hepatitis D (HDV), HIV, human papillomavirus (HPV),respiratory syncytial virus (RSV), severe acute respiratory syndrome(SARS), influenza, parainfluenza, cytomegalovirus, dengue, herpessimplex virus-1, herpes simplex virus-2, leishmania infection, andrespiratory syncytial virus.

In certain embodiments, a method of treating or preventing a viralinfection is provided, comprising administering to an individual (e.g. ahuman) a therapeutically effective amount a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In oneembodiment, the method can be used to induce an immune response againstmultiple epitopes of a viral infection in a human. Induction of animmune response against viral infection can be assessed using anytechnique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present disclosure include, among others,detecting a decrease in viral load or antigen in a subject's serum,detection of IFN-gamma-secreting peptide specific T cells, and detectionof elevated levels of one or more liver enzymes, such as alaninetransferase (ALT) and aspartate transferase (AST). In one embodiment,the detection of IFN-gamma-secreting peptide specific T cells isaccomplished using an ELISPOT assay. Another embodiment includesreducing the viral load associated with HBV infection, including areduction as measured by PCR testing.

In certain embodiments, the present invention provides a method forenhancing the efficacy of a vaccine by co-administering with thevaccine, a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, to anindividual (e.g. a human). In certain embodiments, the compound of thepresent disclosure or a pharmaceutically acceptable salt thereof, may beco-administered with a vaccine to boost the immune response by allowingthe production of a higher amount of antibodies or by allowing a longerlasting protection. In certain embodiments, the compounds of the presentdisclosure, or a pharmaceutically acceptable salt thereof, may be usedas vaccine adjuvants to increase the efficacy and response to theimmunization with a particular antigen. In certain embodiments,co-administering the compounds of the present disclosure, or apharmaceutically acceptable salt thereof, with a vaccine, may influencethe way a vaccine's antigen is presented to the immune system andenhance the vaccine's efficacy.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in medical therapy isprovided. In certain embodiments, a compound of the present disclosureor a pharmaceutically acceptable salt thereof, for use in treating orpreventing a disease or condition responsive to the modulation of TLR-8,is provided. In certain embodiments, the disease or condition is a viralinfection as set forth herein.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a disease or condition responsiveto the modulation of TLR-8, is provided.

In certain embodiments, the present disclosure also provides methods fortreating a hepatitis B viral infection, comprising administering to anindividual (e.g. a human) infected with hepatitis B virus atherapeutically effective amount a compound of the present disclosure ora pharmaceutically acceptable salt thereof. Typically, the individual issuffering from a chronic hepatitis B infection, although it is withinthe scope of the present disclosure to treat people who are acutelyinfected with HBV.

The present disclosure also provides methods for treating a hepatitis Cviral infection, comprising administering to an individual (e.g. ahuman) infected with hepatitis C virus a therapeutically effectiveamount a compound of the present disclosure or a pharmaceuticallyacceptable salt thereof. Typically, the individual is suffering from achronic hepatitis C infection, although it is within the scope of thepresent disclosure to treat people who are acutely infected with HCV.

Treatment of HBV or HCV in accordance with the present disclosuretypically results in the stimulation of an immune response against HBVor HCV in an individual (e.g. a human) being infected with HBV or HCV,respectively, and a consequent reduction in the viral load of HBV or HCVin the infected individual. Examples of immune responses includeproduction of antibodies (e.g., IgG antibodies) and/or production ofcytokines, such as interferons, that modulate the activity of the immunesystem. The immune system response can be a newly induced response, orcan be boosting of an existing immune response. In particular, theimmune system response can be seroconversion against one or more HBV orHCV antigens.

As described more fully herein, compounds of the present disclosure canbe administered with one or more additional therapeutic agent(s) to anindividual (e.g. a human) infected with HBV or HCV. The additionaltherapeutic agent(s) can be administered to the infected individual(e.g.a human) at the same time as a compound of the present disclosureor before or after administration of a compound of the presentdisclosure. For example, in certain embodiments, when used to treat orprevent HCV, a compound of the present disclosure may be administeredwith one or more additional therapeutic agent(s) selected from the groupconsisting of interferons, ribavirin or its analogs, HCV NS3 proteaseinhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV NS5B polymerase,non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors,TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors,pharmacokinetic enhancers, and other drugs for treating HCV, or mixturesthereof. Specific examples are more fully described below.

Further, in certain embodiments, when used to treat or prevent HBV, acompound of the present disclosure may be administered with one or moreadditional therapeutic agent(s) selected from the group consisting ofHBV DNA polymerase inhibitors, toll-like receptor 7 modulators,toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators,Toll-like receptor 3 modulators, interferon alpha ligands, HBsAginhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBVtherapeutic vaccines, HBV prophylactic vaccines, HBV viral entryinhibitors, NTCP inhibitors, antisense oligonucleotide targeting viralmRNA, short interfering RNAs (siRNA), hepatitis B virus E antigeninhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virus,thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core orcapsid protein inhibitors), stimulators of retinoic acid-inducible gene1, stimulators of NOD2, recombinant thymosin alpha-1 and hepatitis Bvirus replication inhibitors, and combinations thereof. Specificexamples are more fully described below.

In certain embodiments, the present disclosure provides a method forameliorating a symptom associated with an HBV infection or HCVinfection, wherein the method comprises administering to an individual(e.g. a human) infected with hepatitis B virus or hepatitis C virus atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, wherein thetherapeutically effective amount is sufficient to ameliorate a symptomassociated with the HBV infection or HCV infection. Such symptomsinclude the presence of HBV virus particles (or HCV virus particles) inthe blood, liver inflammation, jaundice, muscle aches, weakness andtiredness.

In certain embodiments, the present disclosure provides a method forreducing the rate of progression of a hepatitis B viral infection or ahepatitis C virus infection, in an individual (e.g. a human), whereinthe method comprises administering to an individual (e.g. a human)infected with hepatitis B virus or hepatitis C virus a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, wherein the therapeuticallyeffective amount is sufficient to reduce the rate of progression of thehepatitis B viral infection or hepatitis C viral infection. The rate ofprogression of the infection can be followed by measuring the amount ofHBV virus particles or HCV virus particles in the blood.

In certain embodiments, the present disclosure provides a method forreducing the viral load associated with HBV infection or HCV infection,wherein the method comprises administering to an individual (e.g. ahuman) infected with HBV or HCV a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, wherein the therapeutically effective amount is sufficientto reduce the HBV viral load or the HCV viral load in the individual.

In certain embodiments, the present disclosure provides a method ofinducing or boosting an immune response against hepatitis B virus orhepatitis C virus in an individual (e.g. a human), wherein the methodcomprises administering a therapeutically effective amount of a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, to the individual, wherein a new immune response againsthepatitis B virus or hepatitis C virus is induced in the individual, ora preexisting immune response against hepatitis B virus or hepatitis Cvirus is boosted in the individual. Seroconversion with respect to HBVor HCV can be induced in the individual. Examples of immune responsesinclude production of antibodies, such as IgG antibody molecules, and/orproduction of cytokine molecules that modulate the activity of one ormore components of the human immune system.

In certain embodiments, an immune response can be induced against one ormore antigens of HBV or HCV. For example, an immune response can beinduced against the HBV surface antigen (HBsAg), or against the smallform of the HBV surface antigen (small S antigen), or against the mediumform of the HBV surface antigen (medium S antigen), or against acombination thereof. Again by way of example, an immune response can beinduced against the HBV surface antigen (HBsAg) and also against otherHBV-derived antigens, such as the core polymerase or x-protein.

Induction of an immune response against HCV or HBV can be assessed usingany technique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present disclosure include, among others,detecting a decrease in viral load in a individual's serum, such as bymeasuring the amount of HBV DNA or HCV DNA in a subject's blood using aPCR assay, and/or by measuring the amount of anti-HBV antibodies, oranti-HCV antibodies, in the subject's blood using a method such as anELISA.

In certain embodiments, a compound of a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for use in treating or preventing a HBVinfection is provided. In certain embodiments, a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for use in treating or preventing a HCVinfection is provided. In certain embodiments, a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament fortreating or preventing a HBV infection is provided. In certainembodiments, a compound of the present disclosure (e.g. a compound ofFormula (I)), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for treating or preventing a HCV infectionis provided.

In certain embodiments, the present disclosure also provides methods fortreating a Retroviridae viral infection (e.g., an HIV viral infection)in an individual (e.g., a human), comprising administering a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,to the individual.

In certain embodiments, the present disclosure also provides methods fortreating a HIV infection (e.g. a HIV-1 infection), comprisingadministering to an individual (e.g. a human) infected with HIV virus atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV. In certain embodiments, the individual in needthereof is a human who has been infected with HIV but who has notdeveloped AIDS. In certain embodiments, the individual in need thereofis an individual at risk for developing AIDS. In certain embodiments,the individual in need thereof is a human who has been infected with HIVand who has developed AIDS.

In certain embodiments, a method for treating or preventing an HIV viralinfection in an individual (e.g., a human), comprising administering acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, to the individual is provided.

In certain embodiments, a method for inhibiting the replication of theHIV virus, treating AIDS or delaying the onset of AIDS in an individual(e.g., a human), comprising administering a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, to theindividual is provided.

In certain embodiments, a method for preventing an HIV infection in anindividual (e.g., a human), comprising administering a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, tothe individual is provided. In certain embodiments, the individual is atrisk of contracting the HIV virus, such as an individual who has one ormore risk factors known to be associated with of contracting the HIVvirus.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, tothe individual is provided.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof is provided.

In certain embodiments, a compound of the present invention isadministered to a patient where active HIV gene expression has beensuppressed by administration of antiretroviral therapy (includingcombination antiretroviral therapy” or “cART”).

In certain embodiments, a method of reducing the latent HIV reservoir ina human infected with HIV is provided, the method comprisingadministering to the human a pharmaceutically effective amount of acompound of the present disclosure. In certain embodiments, the methodfurther comprises administering one or more anti-HIV agents. In certainembodiments, the method further comprises administering antiretroviraltherapy (including combination antiretroviral therapy” or “cART”). Incertain embodiments, active HIV gene expression in the human has beensuppressed by administration of antiretroviral therapy (includingcombination antiretroviral therapy” or “cART”).

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof for use in medical therapy ofan HIV viral infection (e.g. HIV-1 or the replication of the HIV virus(e.g. HIV-1) or AIDS or delaying the onset of AIDS in an individual(e.g., a human)) is provided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating an HIV viral infection or the replication of theHIV virus or AIDS or delaying the onset of AIDS in an individual (e.g.,a human). One embodiment provides a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of an HIV infection or AIDS or foruse in the therapeutic treatment or delaying the onset of AIDS isprovided.

In certain embodiments, the use of a compound of the present disclosure(e.g. a compound of Formula (I)), or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for an HIV virus infectionin an individual (e.g., a human) is provided. In certain embodiments, acompound of the present disclosure (e.g. a compound of Formula (I)), ora pharmaceutically acceptable salt thereof, for use in the prophylacticor therapeutic treatment of an HIV virus infection is provided.

In certain embodiments, in the methods of use, the administration is toan individual (e.g., a human) in need of the treatment. In certainembodiments, in the methods of use, the administration is to anindividual (e.g., a human) who is at risk of developing AIDS.

Provided herein is a compound of the present disclosure (e.g. a compoundof Formula (I)), or a pharmaceutically acceptable salt thereof, for usein therapy. In one embodiment, the compound of the present disclosure,or a pharmaceutically acceptable salt thereof, is for use in a method oftreating an HIV viral infection or the replication of the HIV virus orAIDS or delaying the onset of AIDS in an individual (e.g., a human).

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HIV in an individual inneed thereof. In certain embodiments, the individual in need thereof isa human who has been infected with HIV. In certain embodiments, theindividual in need thereof is a human who has been infected with HIV butwho has not developed AIDS. In certain embodiments, the individual inneed thereof is an individual at risk for developing AIDS. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV and who has developed AIDS.

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in the therapeutic treatment or delaying the onset of AIDS.

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in the prophylactic or therapeutic treatment of an HIVinfection.

In certain embodiments, the HIV infection is an HIV-1 infection.

Additionally, the compounds of this disclosure are useful in thetreatment of cancer or tumors (including dysplasias, such as uterinedysplasia). These includes hematological malignancies, oral carcinomas(for example of the lip, tongue or pharynx), digestive organs (forexample esophagus, stomach, small intestine, colon, large intestine, orrectum), peritoneum, liver and biliary passages, pancreas, respiratorysystem such as larynx or lung (small cell and non-small cell), bone,connective tissue, skin (e.g., melanoma), breast, reproductive organs(fallopian tube, uterus, cervix, testicles, ovary, or prostate), urinarytract (e.g., bladder or kidney), brain and endocrine glands such as thethyroid. In summary, the compounds of this disclosure are employed totreat any neoplasm, including not only hematologic malignancies but alsosolid tumors of all kinds. In certain embodiments, the compounds areuseful for treating a form of cancer selected from ovarian cancer,breast cancer, head and neck cancer, renal cancer, bladder cancer,hepatocellular cancer, and colorectal cancer.

Hematological malignancies are broadly defined as proliferativedisorders of blood cells and/or their progenitors, in which these cellsproliferate in an uncontrolled manner. Anatomically, the hematologicmalignancies are divided into two primary groups: lymphomas—malignantmasses of lymphoid cells, primarily but not exclusively in lymph nodes,and leukemias—neoplasm derived typically from lymphoid or myeloid cellsand primarily affecting the bone marrow and peripheral blood. Thelymphomas can be sub-divided into Hodgkin's Disease and Non-Hodgkin'slymphoma (NHL). The later group comprises several distinct entities,which can be distinguished clinically (e.g. aggressive lymphoma,indolent lymphoma), histologically (e.g. follicular lymphoma, mantlecell lymphoma) or based on the origin of the malignant cell (e.g. Blymphocyte, T lymphocyte). Leukemias and related malignancies includeacute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia(CLL). Other hematological malignancies include the plasma celldyscrasias including multiple myeloma, and the myelodysplasticsyndromes.

In certain embodiments, the compounds of the present disclosure areuseful in the treatment of B-cell lymphoma, lymphoplasmacytoid lymphoma,fallopian tube cancer, head and neck cancer, ovarian cancer, andperitoneal cancer.

In certain embodiments, the compounds of the present disclosure areuseful in the treatment of hepatocellular carcinoma, gastric cancer,and/or colorectal cancer. In certain embodiments, the compounds of thepresent disclosure are useful in the treatment of prostate cancer,breast cancer, and/or ovarian cancer. In certain embodiments, thecompounds of the present disclosure are useful in the treatment ofrecurrent or metastatic squamous cell carcinoma.

In certain embodiments, a method of treating a hyperproliferativedisease, comprising administering to an individual (e.g. a human) inneed thereof a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isprovided. In certain embodiments, the hyperproliferative disease iscancer. In certain embodiments, the cancer is a solid tumor. In certainembodiments, the cancer is selected from ovarian cancer, breast cancer,head and neck cancer, renal cancer, bladder cancer, hepatocellularcancer, and colorectal cancer. In certain embodiments, the cancer is alymphoma. In certain embodiments, the cancer is Hodgkin's lymphoma. Incertain embodiments, the cancer is non-Hodgkin's lymphoma. In certainembodiments, the cancer is B-cell lymphoma. In certain embodiments, thecancer is selected from B-cell lymphoma; fallopian tube cancer, head andneck cancer, ovarian cancer and peritoneal cancer. In certainembodiments, the method further comprises administering one or moreadditional therapeutic agents as more fully described herein.

In certain mebodiments, the cancer is prostate cancer, breast cancer,ovarian cancer, hepatocellular carcinoma, gastric cancer, colorectalcancer and/or recurrent or metastatic squamous cell carcinoma. Incertain mebodiments, the cancer is prostate cancer, breast cancer,and/or ovarian cancer. In certain embodiments, the cancer ishepatocellular carcinoma, gastric cancer, and/or colorectal cancer. Incertain embodiments, the cancer is recurrent or metastatic squamous cellcarcinoma.

V. ADMINISTRATION

In some embodiments, in the methods of use, the administration is to anindividual (e.g., a human) in need of the treatment.

Additional examples of diseases, disorders, or conditions includepsoriasis, systemic lupus erythematosusand allergic rhinitis

In one embodiment, the compound of the present disclosure, or apharmaceutically acceptable salt thereof, is for use in a method oftreating a hyperproliferative disease (e.g. cancer) in an individual(e.g., a human).

Also provided herein is the use of a compound of the present disclosure(e.g. a compound of Formula (I)) or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating ahyperproliferative disease (e.g. cancer) is provided.

VI. ADMINISTRATION

One or more of the compounds of the present disclosure (also referred toherein as the active ingredients), can be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal, topical (including buccal and sublingual),transdermal, vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary withfor example the condition of the recipient. An advantage of certaincompounds disclosed herein is that they are orally bioavailable and canbe dosed orally.

A compound of the present disclosure, such as a compound of Formula (I),may be administered to an individual in accordance with an effectivedosing regimen for a desired period of time or duration, such as atleast about one month, at least about 2 months, at least about 3 months,at least about 6 months, or at least about 12 months or longer. In onevariation, the compound is administered on a daily or intermittentschedule for the duration of the individual's life.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In certain embodiments, the compound is administeredonce daily.

In certain embodiments, methods for treating or preventing a disease orcondition in a human are provided, comprising administering to the humana therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, four, one or two, one to three, or one to four)additional therapeutic agents. As modulators of TLR-8 may be used in thetreatment of various diseases or condutions, the particular identity ofthe additional therapeutic agents will depend on the particular diseaseor condition being treated.

The compound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IV), (IVa), (IVb), (IVc), or (IVd) can be administered by anyuseful route and means, such as by oral or parenteral (e.g.,intravenous) administration. Therapeutically effective amounts of thecompound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb),(IV), (IVa), (IVb), (IVc), or (IVd) are from about 0.00001 mg/kg bodyweight per day to about 10 mg/kg body weight per day, such as from about0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day,or such as from about 0.001 mg/kg body weight per day to about 1 mg/kgbody weight per day, or such as from about 0.01 mg/kg body weight perday to about 1 mg/kg body weight per day, or such as from about 0.05mg/kg body weight per day to about 0.5 mg/kg body weight per day, orsuch as from about 0.3 μg to about 30 mg per day, or such as from about30 μg to about 300 μg per day.

A compound of the present disclosure (e.g., any compound of Formula (I))may be combined with one or more additional therapeutic agents in anydosage amount of the compound of the present disclosure (e.g., from 1 mgto 1000 mg of compound). Therapeutically effective amounts of thecompound of Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb),(IV), (IVa), (IVb), (IVc), or (IVd), are from about 0.01 mg per dose toabout 1000 mg per dose, such as from about 0.01 mg per dose to about 100mg per dose, or such as from about 0.1 mg per dose to about 100 mg perdose, or such as from about 1 mg per dose to about 100 mg per dose, orsuch as from about 1 mg per dose to about 10 mg per dose. Othertherapeutically effective amounts of the compound of Formula (J), (I),(II), (IIa), (lib), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or(IVd) are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about100 mg per dose. Other therapeutically effective amounts of the compoundof Formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV),(IVa), (IVb), (IVc), or (IVd) are about 100 mg per dose, or about 125,150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg perdose. A single dose can be administered hourly, daily, or weekly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth.

The frequency of dosage of the compound of Formula (J), (I), (II),(IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd)will be determined by the needs of the individual patient and can be,for example, once per day or twice, or more times, per day.Administration of the compound continues for as long as necessary totreat the HBV or HCV infection. For example, Compound I can beadministered to a human being infected with HBV or HCV for a period offrom 20 days to 180 days or, for example, for a period of from 20 daysto 90 days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound ofFormula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV),(IVa), (IVb), (IVc), or (IVd), followed by a period of several or moredays during which a patient does not receive a daily dose of thecompound. For example, a patient can receive a dose of the compoundevery other day, or three times per week. Again by way of example, apatient can receive a dose of the compound each day for a period of from1 to 14 days, followed by a period of 7 to 21 days during which thepatient does not receive a dose of the compound, followed by asubsequent period (e.g., from 1 to 14 days) during which the patientagain receives a daily dose of the compound. Alternating periods ofadministration of the compound, followed by non-administration of thecompound, can be repeated as clinically required to treat the patient.

In one embodiment, pharmaceutical compositions comprising a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,in combination with one or more (e.g., one, two, three, four, one ortwo, one to three, or one to four) additional therapeutic agents, and apharmaceutically acceptable excipient are provided.

In one embodiment, kits comprising a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, in combination with oneor more (e.g., one, two, three, four, one or two, one to three, or oneto four) additional therapeutic agents are provided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In certain embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In certain embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In certain embodiments, a compound of the present disclosure isadministered with one or more additional therapeutic agents.Co-administration of a compound of the present disclosure with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of a compound of the present disclosure andone or more additional therapeutic agents, such that therapeuticallyeffective amounts of the compound disclosed herein and one or moreadditional therapeutic agents are both present in the body of thepatient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compound ofthe present disclosure is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound of the presentdisclosure within seconds or minutes. In some embodiments, a unit doseof a compound of the present disclosure is administered first, followed,after a period of hours (e.g., 1-12 hours), by administration of a unitdose of one or more additional therapeutic agents. In other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of a compound of the present disclosure.

VII. COMBINATION THERAPY FOR HBV

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three or one to four) additional therapeuticagents. In one embodiment, a method for treating an HBV infection in ahuman having or at risk of having the infection is provided, comprisingadministering to the human a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more (e.g., one, two, three, four, one or two, one to three orone to four) additional therapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents which are suitable for treating an HBVinfection. In certain embodiments, one or more additional therapeuticagents includes, for example, one, two, three, four, one or two, one tothree or one to four additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be ananti-HBV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HBVcombination drugs, HBV DNA polymerase inhibitors, immunomodulators,toll-like receptor modulators (modulators of TLR-1, TLR-2, TLR-3, TLR-4,TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13),interferon alpha receptor ligands, hyaluronidase inhibitors, recombinantIL-7, hepatitis B surface antigen (HBsAg) inhibitors, compoundstargeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors, HBVtherapeutic vaccines, HBV prophylactic vaccines, HBV viral entryinhibitors, NTCP (Na+-taurocholate cotransporting polypeptide)inhibitors, antisense oligonucleotide targeting viral mRNA, shortinterfering RNAs (siRNA), miRNA gene therapy agents, endonucleasemodulators, inhibitors of ribonucleotide reductase, hepatitis B virus Eantigen inhibitors, recombinant scavenger receptor A (SRA) proteins, Srckinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetichairpin RNAs (sshRNAs), HBV antibodies including HBV antibodiestargeting the surface antigens of the hepatitis B virus and bispecificantibodies and “antibody-like” therapeutic proteins (such as DARTs®,Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokineantagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBVcore or capsid protein inhibitors), stimulators of retinoicacid-inducible gene 1, stimulators of NOD2, stimulators of NOD1,Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin betareceptor activators, Natural Killer Cell Receptor 2B4 inhibitors,Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxicT-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killercell lectin-like receptor subfamily G member 1 inhibitors, TIM-3inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors,PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, recombinantthymosin alpha-1, BTK inhibitors, modulators of TIGIT, modulators ofCD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27,modulators of CD70, modulators of OX40, modulators of NKG2D, modulatorsof Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A,modulators of GITR, modulators of CD160, modulators of HEVEM, modulatorsof CD161, modulators of Axl, modulators of Mer, modulators of Tyro, genemodifiers or editors such as CRISPR (including CRISPR Cas9), zinc fingernucleases or synthetic nucleases (TALENs), Hepatitis B virus replicationinhibitors, compounds such as those disclosed in U.S. Publication No.2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248(Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead Sciences),U.S. Pat. No. 8,722,054 (Gilead Sciences), U.S. Publication No.2014/0045849 (Janssen), U.S. Publication No. 2014/0073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), U.S. Publication No. 2014/0350031 (Janssen), WO2014/023813(Janssen), U.S. Publication No. 2008/0234251 (Array Biopharma), U.S.Publication No. 2008/0306050 (Array Biopharma), U.S. Publication No.2010/0029585 (Ventirx Pharma), U.S. Publication No. 2011/0092485(Ventirx Pharma), US2011/0118235 (Ventirx Pharma), U.S. Publication No.2012/0082658 (Ventirx Pharma), U.S. Publication No. 2012/0219615(Ventirx Pharma), U.S. Publication No. 2014/0066432 (Ventirx Pharma),U.S. Publication No. 2014/0088085 (Ventirx Pharma), U.S. Publication No.2014/0275167 (Novira Therapeutics), U.S. Publication No. 2013/0251673(Novira Therapeutics), U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S.Publication No. 2014/0030221 (Gilead Sciences), U.S. Publication No.2013/0344030 (Gilead Sciences), U.S. Publication No. 2013/0344029(Gilead Sciences), U.S. Publication No. 2014/0343032 (Roche),WO2014037480 (Roche), U.S. Publication No. 2013/0267517 (Roche),WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen),WO2014033167 (Janssen), U.S. Publication No. 2014/0330015 (OnoPharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical),U.S. Publication No. 2013/0217880 (Ono pharmaceutical), and other drugsfor treating HBV, and combinations thereof. In some embodiments, theadditional therapeutic agent is further selected from hepatitis Bsurface antigen (HBsAg) secretion or assembly inhibitors, TCR-likeantibodies, IDO inhibitors, cccDNA epigenetic modifiers, IAPsinhibitors, SMAC mimetics, and compounds such as those disclosed inUS20100015178 (Incyte),

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HBV combination drugs, HBV DNA polymeraseinhibitors, toll-like receptor 7 modulators, toll-like receptor 8modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3modulators, interferon alpha receptor ligands, HBsAg inhibitors,compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeuticvaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCPinhibitors, antisense oligonucleotide targeting viral mRNA, shortinterfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodiestargeting the surface antigens of the hepatitis B virus, thymosinagonists, cytokines, nucleoprotein inhibitors (HBV core or capsidprotein inhibitors), stimulators of retinoic acid-inducible gene 1,stimulators of NOD2, stimulators of NOD1, recombinant thymosin alpha-1,BTK inhibitors, and hepatitis B virus replication inhibitors, andcombinations thereof. In certain embodiments, the additional therapeuticis selected from hepatitis B surface antigen (HBsAg) secretion orassembly inhibitors and IDO inhibitors.

In certain embodiments a compound of the present disclosure (e.g. acompound of Formula (I)) is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating HBV. In certainembodiments, the tablet can contain another active ingredient fortreating HBV, such as HBV DNA polymerase inhibitors, immunomodulators,toll-like receptor modulators (modulators of TLR-1, TLR-2, TLR-3, TLR-4,TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13),modulators of tlr7, modulators of tlr8, modulators of tlr7 and tlr8,interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis Bsurface antigen (HBsAg) inhibitors, compounds targeting hepatitis B coreantigen (HbcAg), cyclophilin inhibitors, HBV viral entry inhibitors,NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors,endonuclease modulators, inhibitors of ribonucleotide reductase,hepatitis B virus E antigen inhibitors, Src kinase inhibitors, HBxinhibitors, cccDNA inhibitors, CCR2 chemokine antagonists, thymosinagonists, nucleoprotein inhibitors (HBV core or capsid proteininhibitors), stimulators of retinoic acid-inducible gene 1, stimulatorsof NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists,PI3K inhibitors, lymphotoxin beta receptor activators, Natural KillerCell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors,CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamilyG member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuatorinhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulatorsof B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR,modulators of CD160, modulators of HEVEM, modulators of CD161,modulators of Axl, modulators of Mer, modulators of Tyro, and HepatitisB virus replication inhibitors, and combinations thereof. In certainembodiments, the tablet can contain another active ingredient fortreating HBV, such as hepatitis B surface antigen (HBsAg) secretion orassembly inhibitors, cccDNA epigenetic modifiers, IAPs inhibitors, SMACmimetics, and IDO inhibitors.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Combination drugs selected from the group consisting of    tenofovir disoproxil fumarate+emtricitabine (TRUVADA®);    adefovir+clevudine and GBV-015, as well as combination drugs    selected from ABX-203+lamivudine+PEG-IFNalpha,    ABX-203+adefovir+PEG-IFNalpha, and INO-9112+RG7944 (INO-1800);-   (2) HBV DNA polymerase inhibitors selected from the group consisting    of besifovir, entecavir (Baraclude®), adefovir (Hepsera®), tenofovir    disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir,    tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir    alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil    fumarate, tenofovir octadecyloxyethyl ester, telbivudine (Tyzeka®),    pradefovir, Clevudine, emtricitabine (Emtriva®), ribavirin,    lamivudine (Epivir-HBV®), phosphazide, famciclovir, SNC-019754,    FMCA, fusolin, AGX-1009 and metacavir, as well as HBV DNA polymerase    inhibitors selected from AR-II-04-26 and HS-10234;-   (3) Immunomodulators selected from the group consisting of    rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil    (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil    (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10,    ribavirin, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1,    MOR-22, BMS-936559 and IR-103, as well as immunomodulators selected    from INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1,    MOR-22, BMS-936559, RO-7011785, RO-6871765 and IR-103;-   (4) Toll-like receptor 7 modulators selected from the group    consisting of GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434,    DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop,    TMX-30X, TMX-202 RG-7863 and RG-7795;-   (5) Toll-like receptor 8 modulators selected from the group    consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465,    IMO-4200, VTX-763, VTX-1463;-   (6) Toll-like receptor 3 modulators selected from the group    consisting of rintatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon,    Riboxxim and ND-1.1;-   (7) Interferon alpha receptor ligands selected from the group    consisting of interferon alpha-2b (Intron A®), pegylated interferon    alpha-2a (Pegasys®), interferon alpha 1b (Hapgen®), Veldona,    Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),    P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co    (recombinant super compound interferon), Ypeginterferon alfa-2b    (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-Intron®),    Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon    alfa-nl(Humoferon®), interferon beta-1a (Avonex®), Shaferon,    interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b    (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG,    BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion,    Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN,    Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano,    Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A,    Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b    (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon,    Uniferon, Urifron, interferon alfa-2b (Changchun Institute of    Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng    Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and    Interapo (Interapa);-   (8) Hyaluronidase inhibitors selected from the group consisting of    astodrimer;-   (9) Modulators of IL-10;-   (10) HBsAg inhibitors selected from the group consisting of    HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP 9AC, REP-9C and REP    9AC′, as well as HBsAg inhibitors selected from REP-9, REP-2139,    REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053,    REP-2031 and REP-006 and REP-9AC′-   (11) Toll like receptor 9 modulators selected from CYT003, as well    as Toll like receptor 9 modulators selected from CYT-003, IMO-2055,    IMO-2125, IMO-3100, IMO-8400, IMO-9200, agatolimod, DIMS-9054,    DV-1179, AZD-1419, MGN-1703, and CYT-003-QbG10;-   (12) Cyclophilin inhibitors selected from the group consisting of    OCB-030, SCY-635 and NVP-018;-   (13) HBV Prophylactic vaccines selected from the group consisting of    Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B,    D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine,    Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay,    hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07,    GSK-223192A, Engerix B®, recombinant hepatitis B vaccine    (intramuscular, Kangtai Biological Products), recombinant hepatitis    B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan    Biological Engineering), Bimmugen, Euforavac, Eutravac,    anrix-DTaP—IPV-Hep B, Infanrix-DTaP—IPV-Hep B-Hib, Pentabio Vaksin    DTP—HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep    B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac    HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,    SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,    Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine,    and DTaP-rHB-Hib vaccine;-   (14) HBV Therapeutic vaccines selected from the group consisting of    HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous),    ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine    (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC,    Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB,    VGX-6200, FP-02, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine,    Mega-CD40L-adjuvanted vaccine, HepB-v, NO-1800, recombinant    VLP-based therapeutic vaccine (HBV infection, VLP Biotech),    AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV, as well    as HBV Therapeutic vaccines selected from FP-02.2 and RG7944    (INO-1800);-   (15) HBV viral entry inhibitor selected from the group consisting of    Myrcludex B;-   (16) Antisense oligonucleotide targeting viral mRNA selected from    the group consisting of ISIS-HBVRx;-   (17) short interfering RNAs (siRNA) selected from the group    consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi and    ARC-520;-   (18) Endonuclease modulators selected from the group consisting of    PGN-514;-   (19) Inhibitors of ribonucleotide reductase selected from the group    consisting of Trimidox;-   (20) Hepatitis B virus E antigen inhibitors selected from the group    consisting of wogonin;-   (21) HBV antibodies targeting the surface antigens of the hepatitis    B virus selected from the group consisting of GC-1102, XTL-17,    XTL-19, XTL-001, KN-003 and fully human monoclonal antibody therapy    (hepatitis B virus infection, Humabs BioMed), as well as HBV    antibodies targeting the surface antigens of the hepatitis B virus    selected from IV Hepabulin SN;-   (22) HBV antibodies including monoclonal antibodies and polyclonal    antibodies selected from the group consisting of Zutectra, Shang    Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B,    Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24,    hepatitis B immunoglobulin (intravenous, pH4, HBV infection,    Shanghai RAAS Blood Products) and Fovepta (BT-088);-   (23) CCR2 chemokine antagonists selected from the group consisting    of propagermanium;-   (24) Thymosin agonists selected from the group consisting of    Thymalfasin;-   (25) Cytokines selected from the group consisting of recombinant    IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human    interleukin-2 (Shenzhen Neptunus) and celmoleukin, as well as    cytokines selected from IL-15, IL-21, IL-24;-   (26) Nucleoprotein inhibitors (HBV core or capsid protein    inhibitors) selected from the group consisting of NVR-1221,    NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23;-   (27) Stimulators of retinoic acid-inducible gene 1 selected from the    group consisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350,    ORI-7537, ORI-9020, ORI-9198 and ORI-7170;-   (28) Stimulators of NOD2 selected from the group consisting of    SB-9200;-   (29) Recombinant thymosin alpha-1 selected from the group consisting    of NL-004 and PEGylated thymosin alpha 1;-   (30) Hepatitis B virus replication inhibitors selected from the    group consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie;-   (31) PI3K inhibitors selected from the group consisting of    idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib,    rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib,    duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,    panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093,    pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,    RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib,    LY-3023414, SAR-260301 and CLR-1401;-   (32) cccDNA inhibitors selected from the group consisting of    BSBI-25;-   (33) PD-L1 inhibitors selected from the group consisting of    MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C,    TSR-042, ALN-PDL, STI-A1014 and BMS-936559;-   (34) PD-1 inhibitors selected from the group consisting of    nivolumab, pembrolizumab, pidilizumab, BGB-108 and mDX-400;-   (35) BTK inhibitors selected from the group consisting of ACP-196,    dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111,    MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536,    AC-0025;-   (36) Other drugs for treating HBV selected from the group consisting    of gentiopicrin (gentiopicroside), nitazoxanide, birinapant, NOV-205    (Molixan; BAM-205), Oligotide, Mivotilate, Feron, levamisole, Ka Shu    Ning, Alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm,    KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5),    HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA,    Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang), picroside,    GA5 NM-HBV, DasKloster-0039, hepulantai, IMB-2613, TCM-800B and    ZH-2N, as well as other drugs for treating HBV selected from reduced    glutathione, and RO-6864018; and-   (37) The compounds disclosed in US20100143301 (Gilead Sciences),    US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences),    U.S. Pat. No. 8,722,054 (Gilead Sciences), US20140045849 (Janssen),    US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221    (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen),    WO2014/023813 (Janssen), US20080234251 (Array Biopharma),    US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma),    US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),    US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),    US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma),    US20140275167 (Novira therapeutics), US20130251673 (Novira    therapeutics), U.S. Pat. No. 8,513,184 (Gilead Sciences),    US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences),    US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480    (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176    (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen),    US20140330015 (Ono pharmaceutical), US20130079327 (Ono    pharmaceutical), and US20130217880 (Ono pharmaceutical), and the    compounds disclosed in US20100015178 (Incyte).

Also included in the list above are:

-   (38) IDO inhibitors selected from the group consisting of    epacadostat (INCB24360), F-001287, resminostat (4SC-201), SN-35837,    NLG-919, GDC-0919, and indoximod;-   (39) Arginase inhibitors selected from CB-1158, C-201, and    resminostat; and-   (40) Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors    selected from ipilumimab, belatacept, PSI-001, PRS-010,    tremelimumab, and JHL-1155.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In a specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor. In another specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with an HBV DNA polymerase inhibitor and at least oneadditional therapeutic agent selected from the group consisting of:immunomodulators, toll-like receptor modulators (modulators of TLR-1,TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11,TLR-12 and TLR-13), interferon alpha receptor ligands, hyaluronidaseinhibitors, recombinant IL-7, HBsAg inhibitors, compounds targetingHbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBVprophylactic vaccines HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitorsof ribonucleotide reductase, Hepatitis B virus E antigen inhibitors,recombinant scavenger receptor A (SRA) proteins, src kinase inhibitors,HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs(sshRNAs), HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®,Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokine antagonists,thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core orcapsid protein inhibitors), stimulators of retinoic acid-inducible gene1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors,STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators,Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associatedprotein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulatorsof B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR,modulators of CD160, modulators of HEVEM, modulators of CD161,modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiersor editors such as CRISPR (including CRISPR Cas9), zinc finger nucleasesor synthetic nucleases (TALENs), and Hepatitis B virus replicationinhibitors. In certain embodiments the at least one additionaltherapeutic agent is further selected from hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, TCR-like antibodies, cccDNAepigenetic modifiers, IAPs inhibitors, SMAC mimetics, and IDOinhibitors.

In another specific embodiment, a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least one additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, short interfering RNAs(siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs(sshRNAs), and nucleoprotein inhibitors (HBV core or capsid proteininhibitors).

In another specific embodiment, a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of: immunomodulators, toll-like receptormodulators (modulators of TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6,TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), HBsAginhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3Kinhibitors and stimulators of NOD2, and one or two additionaltherapeutic agents selected from the group consisting of: HBV viralentry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors,HBV antibodies targeting the surface antigens of the hepatitis B virus,short interfering RNAs (siRNA), miRNA gene therapy agents, shortsynthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV coreor capsid protein inhibitors). In certain embodiments one or twoadditional therapeutic agents is further selected from hepatitis Bsurface antigen (HBsAg) secretion or assembly inhibitors, TCR-likeantibodies, and IDO inhibitors.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from adefovir(Hepsera®), tenofovir disoproxil fumarate+emtricitabine (TRUVADA®),tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®),lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine(Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferonalpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylatedinterferon alpha-2a (Pegasys®), interferon alfa-nl (Humoferon®),ribavirin, interferon beta-la (Avonex®), Bioferon, Ingaron, Inmutag(Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferonalfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma),Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®)

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with entecavir(Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate(Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) orlamivudine (Epivir-HBV®).

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof is combined with a PD-1inhibitor. In a particular embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof is combinedwith a PD-L1 inhibitor. In a particular embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof iscombined with an IDO inhibitor. In a particular embodiment, a compoundof the present disclosure, or a pharmaceutically acceptable salt thereofis combined with an IDO inhibitor and a PD-1 inhibitor. In a particularembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with an IDO inhibitor and a PD-L1inhibitor. In a particular embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith a TLR7 modulator, such as GS-9620.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a TLR7modulator and an IDO inhibitor. In a particular embodiment, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is combined with a TLR7 modulator such as GS-9620 and an IDOinhibitor such as epacadostat.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with(4-amino-2-butoxy-8-({3-[(pyrrolidin-1-yl)methyl]phenyl}methyl)-7,8-dihydropteridin-6(5H)-one)or a pharmaceutically acceptable salt thereof.

As used herein, GS-9620(4-amino-2-butoxy-8-({3-[(pyrrolidin-1-yl)methyl]phenyl}methyl)-7,8-dihydropteridin-6(5H)-one),includes pharmaceutically acceptable salts thereof. J. Med. Chem., 2013,56 (18), pp 7324-7333.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxilfumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and atleast one additional therapeutic agent selected from the groupconsisting of immunomodulators, toll-like receptor modulators(modulators of TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8,TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), interferon alpha receptorligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors,compounds targeting HbcAg, cyclophilin inhibitors, HBV Therapeuticvaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCPinhibitors, antisense oligonucleotide targeting viral mRNA, shortinterfering RNAs (siRNA), miRNA gene therapy agents, endonucleasemodulators, inhibitors of ribonucleotide reductase, Hepatitis B virus Eantigen inhibitors, recombinant scavenger receptor A (SRA) proteins, srckinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetichairpin RNAs (sshRNAs), HBV antibodies including HBV antibodiestargeting the surface antigens of the hepatitis B virus and bispecificantibodies and “antibody-like” therapeutic proteins (such as DARTs®,Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokineantagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBVcore or capsid protein inhibitors), stimulators of retinoicacid-inducible gene 1, stimulators of NOD2, stimulators of NOD1,recombinant thymosin alpha-1, Arginase-1 inhibitors, STING agonists,PI3K inhibitors, lymphotoxin beta receptor activators, Natural KillerCell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors,CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamilyG member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuatorinhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors,PEG-Interferon Lambd, BTK inhibitors, modulators of TIGIT, modulators ofCD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27,modulators of CD70, modulators of OX40, modulators of NKG2D, modulatorsof Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A,modulators of GITR, modulators of CD160, modulators of HEVEM, modulatorsof CD161, modulators of Axl, modulators of Mer, modulators of Tyro, genemodifiers or editors such as CRISPR (including CRISPR Cas9), zinc fingernucleases or synthetic nucleases (TALENs), a and Hepatitis B virusreplication inhibitors. In certain embodiments, the at least oneadditional therapeutic agent is further selected from hepatitis Bsurface antigen (HBsAg) secretion or assembly inhibitors, TCR-likeantibodies, IDO inhibitors, cccDNA epigenetic modifiers, IAPsinhibitors, and SMAC mimetics.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxilfumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and atleast a one additional therapeutic agent selected from the groupconsisting of peginterferon alfa-2b (PEG-Intron®), Multiferon®,interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®),pegylated interferon alpha-2a (Pegasys®), interferonalfa-nl(Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon,Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra,Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b(BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum,VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, interferon alfa-2b (IFN, LaboratoriosBioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep,interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon,interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferonalfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferonalfa-2b (Changchun Institute of Biological Products), Anterferon,Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxilfumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and atleast one additional therapeutic agent selected from the groupconsisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNAgene therapy agents, short synthetic hairpin RNAs (sshRNAs), andnucleoprotein inhibitors (HBV core or capsid protein inhibitors).

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxilfumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), one ortwo additional therapeutic agents selected from the group consisting of:immunomodulators, toll-like receptor modulators (modulators of TLR-1,TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11,TLR-12 and TLR-13), HBsAg inhibitors, HBV therapeutic vaccines, HBVantibodies including HBV antibodies targeting the surface antigens ofthe hepatitis B virus and bispecific antibodies and “antibody-like”therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), cyclophilin inhibitors, stimulators ofretinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors,Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2, and oneor two additional therapeutic agents selected from the group consistingof: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, HBV antibodies targeting the surface antigens of thehepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapyagents, short synthetic hairpin RNAs (sshRNAs), and nucleoproteininhibitors (HBV core or capsid protein inhibitors). In certainembodiments, the one or two additional therapeutic agents is furtherselected from hepatitis B surface antigen (HBsAg) secretion or assemblyinhibitors, TCR-like antibodies, and IDO inhibitors.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 10 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 25 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compoundof the present disclosure (e.g., a compound of Formula (I)) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed. Acompound of the present disclosure (e.g., a compound of Formula (I)) maybe combined with the agents provided herein in any dosage amount of thecompound (e.g. from about 1 mg to about 150 mg of compound) the same asif each combination of dosages were specifically and individuallylisted.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 100-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250;150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350;250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with 300 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 250 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 150 mg tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, or tenofovir disoproxil. A compound of the presentdisclosure (e.g., a compound of Formula (I)) may be combined with theagents provided herein in any dosage amount of the compound (e.g., from50 mg to 500 mg of compound) the same as if each combination of dosageswere specifically and individually listed. A compound of the presentdisclosure (e.g., a compound of Formula (I)) may be combined with theagents provided herein in any dosage amount of the compound (e.g., fromabout 1 mg to about 150 mg of compound) the same as if each combinationof dosages were specifically and individually listed.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional active ingredients for treating HBV, for usein a method of treating or preventing HBV.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HBV, wherein the compound,or a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with one or more additionaltherapeutic agents fort for treating HBV.

VIII. COMBINATION THERAPY FOR HCV

In certain embodiments, a method for treating or preventing an HCVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HCV infection in a human having orat risk of having the infection is provided, comprising administering tothe human a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HCV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents which are suitable for treating an HCVinfection.

In the above embodiments, the additional therapeutic agent may be ananti-HCV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of interferons,ribavirin or its analogs, HCV NS3 protease inhibitors, HCV NS4 proteaseinhibitors, HCV NS3/NS4 protease inhibitors, alpha-glucosidase 1inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors ofHCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase,HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRESinhibitors, and pharmacokinetic enhancers, compounds such as thosedisclosed in US2010/0310512, US2013/0102525, and WO2013/185093, orcombinations thereof.

In certain embodiments a compound of the present disclosure (e.g., acompound of Formula (I)) is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating HCV. In certainembodiments, the tablet can contain another active ingredient fortreating HCV, such as interferons, ribavirin or its analogs, HCV NS3protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV NS5B polymerase,non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors,TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, andpharmacokinetic enhancers, or combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Interferons selected from the group consisting of pegylated    rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys),    rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon    alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin),    interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon),    interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234),    interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b    (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated    interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon    lambda (PEGylated IL-29), or belerofon, IFN alpha-2b XL, rIFN-alpha    2a, consensus IFN alpha, infergen, rebif, pegylated IFN-beta, oral    interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta, and    infergen+actimmuneribavirin and ribavirin analogs, e.g., rebetol,    copegus, VX-497, and viramidine (taribavirin);-   (2) Ribavirin and its analogs selected from the group consisting of    ribavirin (Rebetol, Copegus), and taribavirin (Viramidine);-   (3) NS5A inhibitors selected from the group consisting of    Compound A. 1 (described below), Compound A.2 (described below),    Compound A.3 (described below), ABT-267, Compound A.4 (described    below), JNJ-47910382, daclatasvir (BMS-790052), ABT-267, Samatasvir,    MK-8742, MK-8404, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102,    A-831, A-689, AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052;-   (4) NS5B polymerase inhibitors selected from the group consisting of    sofosbuvir (GS-7977), Compound A.5 (described below), Compound A.6    (described below), ABT-333, Compound A.7 (described below), ABT-072,    Compound A.8 (described below), tegobuvir (GS-9190), GS-9669,    TMC647055, ABT-333, ABT-072, setrobuvir (ANA-598), IDX-21437,    filibuvir (PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127,    valopicitabine (NM-283), PSI-6130 (R1656), PSI-7851, BCX-4678,    nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759,    GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837,    GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, BILB-1941,    AL-335, AL-516 and ACH-3422;-   (5) Protease (NS3, NS3-NS4) inhibitors selected from the group    consisting of Compound A.9, Compound A. 10, Compound A. 11, ABT-450,    Compound A. 12 (described below), simeprevir (TMC-435), boceprevir    (SCH-503034), narlaprevir (SCH-900518), vaniprevir (MK-7009),    MK-5172, danoprevir (ITMN-191), sovaprevir (ACH-1625), neceprevir    (ACH-2684), Telaprevir (VX-950), VX-813, VX-500, faldaprevir    (BI-201335), asunaprevir (BMS-650032), BMS-605339, VBY-376,    PHX-1766, YH5531, BILN-2065, and BILN-2061;-   (6) Alpha-glucosidase 1 inhibitors selected from the group    consisting of celgosivir (MX-3253), Miglitol, and UT-231B;-   (7) Hepatoprotectants selected from the group consisting of    emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin, and    MitoQ;-   (8) TLR-7 agonists selected from the group consisting of imiquimod,    852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), and SM-360320;-   (9) Cyclophillin inhibitors selected from the group consisting of    DEBIO-025, SCY-635, and NIM811;-   (10) HCV IRES inhibitors selected from the group consisting of    MCI-067;-   (11) Pharmacokinetic enhancers selected from the group consisting of    BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and    roxythromycin; and-   (12) Other anti-HCV agents selected from the group consisting of    thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401    (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),    GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,    ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,    EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106    (ONO-4538), Oglufanide, VX-497 (merimepodib) NIM811, benzimidazole    derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine    derivatives;

Compound A. 1 is an inhibitor of the HCV NS5A protein and is representedby the following chemical structure:

(see, e.g., U.S. Application Publication No. 20100310512 A1).

Compound A.2 is an NS5A inhibitor and is represented by the followingchemical structure:

Compound A.3 is an NS5A inhibitor and is represented by the followingchemical structure:

Compound A.4 is an NS5A inhibitor and is represented by the followingchemical structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein.)

Compound A.5 is an NS5B Thumb II polymerase inhibitor and is representedby the following chemical structure:

Compound A.6 is a nucleotide inhibitor prodrug designed to inhibitreplication of viral RNA by the HCV NS5B polymerase, and is representedby the following chemical structure:

Compound A.7 is an HCV polymerase inhibitor and is represented by thefollowing structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

Compound A.8 is an HCV polymerase inhibitor and is represented by thefollowing structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

Compound A.9 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A. 10 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A.11 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A. 12 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

In one embodiment, the additional therapeutic agent used in combinationwith the pharmaceutical compositions as described herein is a HCV NS3protease inhibitor. Non-limiting examples include the following:

In another embodiment, the additional therapeutic agent used incombination with the pharmaceutical compositions as described herein isa cyclophillin inhibitor, including for example, a cyclophilin inhibitordisclosed in WO2013/185093. Non-limiting examples in addition to thoselisted above include the following:

and stereoisomers and mixtures of stereoisomers thereof.

In a specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a HCV NSSBpolymerase inhibitor. In a specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS5B polymerase inhibitor and a HCV NS5A inhibitor.In another specific embodiment, a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, is combined with a HCV NS5Bpolymerase inhibitor, a HCV NS3 protease inhibitor and a HCV NS5Ainhibitor. In another specific embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith a HCV NS5B polymerase inhibitor, a HCV NS4 protease inhibitor and aHCV NS5A inhibitor. In another specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS5B polymerase inhibitor, a HCV NS3/NS4 proteaseinhibitor and a HCV NS5A inhibitor. In another specific embodiment, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with a HCV NS3 protease inhibitor and a HCVNS5A inhibitor. In another specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. Inanother specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a HCV NS3/NS4protease inhibitor and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS3 protease inhibitor,a pharmacokinetic enhancer and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS4 protease inhibitor,a pharmacokinetic enhancer and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS3/NS4 proteaseinhibitor, a pharmacokinetic enhancer and a HCV NS5A inhibitor.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected fromsimeprevir, MK-8742, MK-8408, MK-5172, ABT-450, ABT-267, ABT-333,sofosbuvir, sofosbuvir+ledipasvir, sofosbuvir+GS-5816,sofosbuvir+GS-9857+ledipasvir, ABT-450+ABT-267+ritonavir,ABT-450+ABT-267+ribavirin+ritonavir,ABT-450+ABT-267+ribavirin+ABT-333+ritonavir, ABT-530+ABT-493,MK-8742+MK-5172, MK-8408+MK-3682+MK-5172, MK-8742+MK-3682+MK-5172,daclatasvir, interferon, pegylated interferon, ribavirin, samatasvir,MK-3682, ACH-3422, AL-335, IDX-21437, IDX-21459, tegobuvir, setrobuvir,valopicitabine, boceprevir, narlaprevir, vaniprevir, danoprevir,sovaprevir, neceprevir, telaprevir, faldaprevir, asunaprevir,ledipasvir, GS-5816, GS-9857, ACH-3102, ACH-3422+ACH-3102,ACH-3422+sovaprevir+ACH-3102, asunaprevir, asunaprevir+daclatasvir,AL-516, and vedroprevir.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withsimeprevir. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, isco-administered with MK-8742 or MK-8408. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with MK-5172. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ABT-450, ABT-267, or ABT-333. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withViekirat (a combination of ABT-450, ABT-267, and ritonavir). In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with daclatasvir. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with sofosbuvir. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with Harvoni(sofosbuvir+ledipasvir). In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with sofosbuvir and GS-5816. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with sofosbuvir+GS-9857+ledipasvir. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withABT-450+ABT-267+ribavirin+ritonavir. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered withABT-450+ABT-267+ribavirin+ABT-333+ritonavir. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ABT-530+ABT-493. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered withMK-8408+MK-3682+MK-5172. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with MK-8742+MK-5172. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered with MK-3682. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ACH-3422. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with AL-335. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ACH-3422+ACH-3102. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered withACH-3422+sovaprevir+ACH-3102. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with GS-5816. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with GS-9857. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with IDX-21459. In certain embodiments, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is co-administered with boceprevir. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered with ledipasvir. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with AL-516.

In various methods, Compound A.1 is administered in an amount rangingfrom about 10 mg/day to about 200 mg/day. For example, the amount ofCompound A.1 can be about 30 mg/day, about 45 mg/day, about 60 mg/day,about 90 mg/day, about 120 mg/day, about 135 mg/day, about 150 mg/day,about 180 mg/day. In some methods, Compound A. 1 is administered atabout 90 mg/day. In various methods, Compound A.2 is administered in anamount ranging from about 50 mg/day to about 800 mg/day. For example,the amount of Compound A.2 can be about 100 mg/day, about 200 mg/day, orabout 400 mg/day. In some methods, the amount of Compound A.3 is about10 mg/day to about 200 mg/day. For example, the amount of Compound A.3can be about 25 mg/day, about 50 mg/day, about 75 mg/day, or about 100mg/day.

In various methods, sofosbuvir is administered in an amount ranging fromabout 10 mg/day to about 1000 mg/day. For example, the amount ofsofosbuvir can be about 100 mg/day, about 200 mg/day, about 300 mg/day,about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day,about 800 mg/day. In some methods, sofosbuvir is administered at about400 mg/day.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating HCV, for usein a method of treating or preventing HCV.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HCV, wherein the compoundor a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with one or more additionaltherapeutic agents for treating HCV.

IX. COMBINATION THERAPY FOR HIV

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HIV infection in a human having orat risk of having the infection is provided, comprising administering tothe human a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents which are suitable for treating an HIVinfection. In certain embodiments, one or more additional therapeuticagents includes, for example, one, two, three, four, one or two, one tothree or one to four additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachmentinhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidaseinhibitors, HIV vaccines, HIV maturation inhibitors, latency reversingagents (e.g., histone deacetylase inhibitors, proteasome inhibitors,protein kinase C (PKC) activators, and BRD4 inhibitors), compounds thattarget the HIV capsid (“capsid inhibitors”; e.g., capsid polymerizationinhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7)inhibitors, HIV p24 capsid protein inhibitors), pharmacokineticenhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1modulators, toll like receptors modulators, IL-15 agonists), HIVantibodies, bispecific antibodies and “antibody-like” therapeuticproteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives) including those targeting HIV gpl20 or gp41, combinationdrugs for HIV, HIV p17 matrix protein inhibitors, IL-13 antagonists,Peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfideisomerase inhibitors, Complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,Integrin antagonists, Nucleoprotein inhibitors, Splicing factormodulators, COMM domain containing protein 1 modulators, HIVRibonuclease H inhibitors, Retrocyclin modulators, CDK-9 inhibitors,Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors, Cyclindependent kinase inhibitors Proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, PI3K inhibitors, compounds such as those disclosedin WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University ofPennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285(Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378(Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064(Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497(Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728(Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498(Gilead Sciences) and WO 2013/006792 (Pharma Resources), and other drugsfor treating HIV, and combinations thereof. In some embodiments, theadditional therapeutic agent is further selected from Vif dimerizationantagonists and HIV gene therapy.

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In certain embodiments a compound of the present disclosure isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating HIV. In certain embodiments, the tabletcan contain another active ingredient for treating HIV, such as HIVprotease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors ofreverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, pharmacokinetic enhancers, andcombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Combination drugs selected from the group consisting of ATRIPLA®    (efavirenz+tenofovir disoproxil fumarate+emtricitabine), COMPLERA®    (EVIPLERA®, rilpivirine+tenofovir disoproxil    fumarate+emtricitabine), STRIBILD®    (elvitegravir+cobicistat+tenofovir disoproxil    fumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine,    TRIUMEQ® (dolutegravir+abacavir+lamivudine),    lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine,    atazanavir sulfate+cobicistat, darunavir+cobicistat,    efavirenz+lamivudine+tenofovir disoproxil fumarate, tenofovir    alafenamide hemifumarate+emtricitabine+cobicistat+elvitegravir,    Vacc-4x+romidepsin, darunavir+tenofovir alafenamide    hemifumarate+emtricitabine+cobicistat, APH-0812,    raltegravir+lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir),    atazanavir sulfate+ritonavir, COMBIVIR® (zidovudine+lamivudine,    AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC),    TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC),    TRUVADA® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC),    tenofovir+lamivudine and lamivudine+tenofovir disoproxil fumarate,    as well as combinations drugs selected from dolutegravir+rilpivirine    hydrochloride, atazanavir+cobicistat, tenofovir alafenamide    hemifumarate+emtricitabine, tenofovir alafenamide+emtricitabine,    tenofovir alafenamide hemifumarate+emtricitabine+rilpivirine,    tenofovir alafenamide+emtricitabine+rilpivirine,    doravirine+lamivudine+tenofovir disoproxil fumarate,    doravirine+lamivudine+tenofovir disoproxil;-   (2) HIV protease inhibitors selected from the group consisting of    amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium,    indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir,    nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir,    brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;-   (3) HIV non-nucleoside or non-nucleotide inhibitors of reverse    transcriptase selected from the group consisting of delavirdine,    delavirdine mesylate, nevirapine, etravirine, dapivirine,    doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan and    AIC-292;-   (4) HIV nucleoside or nucleotide inhibitors of reverse transcriptase    selected from the group consisting of VIDEX® and VIDEX® EC    (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine,    zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate,    amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil,    apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir,    tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir    disoproxil hemifumarate, tenofovir alafenamide, tenofovir    alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir,    adefovir dipivoxil, and festinavir;-   (5) HIV integrase inhibitors selected from the group consisting of    curcumin, derivatives of curcumin, chicoric acid, derivatives of    chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of    3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of    aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives    of caffeic acid phenethyl ester, tyrphostin, derivatives of    tyrphostin, quercetin, derivatives of quercetin, raltegravir,    elvitegravir, dolutegravir and cabotegravir, as well as HIV    integrase inhibitors selected from JTK-351;-   (6) HIV non-catalytic site, or allosteric, integrase inhibitors    (NCINI) selected from the group consisting of CX-05168, CX-05045 and    CX-14442;-   (7) HIV gp41 inhibitors selected from the group consisting of    enfuvirtide, sifuvirtide and albuvirtide;-   (8) HIV entry inhibitors selected from the group consisting of    cenicriviroc;-   (9) HIV gp120 inhibitors selected from the group consisting of    Radha-108 (Receptol) and BMS-663068;-   (10) CCR5 inhibitors selected from the group consisting of    aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir    (RAP-101), TBR-220 (TAK-220), nifeviroc (TD-0232), TD-0680, and vMIP    (Haimipu);-   (11) CD4 attachment inhibitors selected from the group consisting of    ibalizumab;-   (12) CXCR4 inhibitors selected from the group consisting of    plerixafor, ALT-1188, vMIP and Haimipu;-   (13) Pharmacokinetic enhancers selected from the group consisting of    cobicistat and ritonavir;-   (14) Immune-based therapies selected from the group consisting of    dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin    (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon    alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea,    mycophenolate mofetil (MPA) and its ester derivative mycophenolate    mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer    polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like    receptors modulators (TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6,    TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13),    rintatolimod and IR-103;-   (15) HIV vaccines selected from the group consisting of peptide    vaccines, recombinant subunit protein vaccines, live vector    vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion    vaccine), CD4-derived peptide vaccines, vaccine combinations, rgp120    (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune,    ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409,    Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5    (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine,    AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51,    poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06),    AGS-004, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag    vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2,    NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP,    GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4    (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01,    SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR,    ETV-01 and DNA-Ad5 gag/pol/nef/nev (HVTN505), as well as HIV    vaccines selected from monomeric gp120 HIV-1 subtype C vaccine    (Novartis), HIV-TriMix-mRNA, MVATG-17401, ETV-01, CDX-1401, and    rcAd26.MOS1.HIV-Env;-   (16) HIV antibodies, bispecific antibodies and “antibody-like”    therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®,    TandAbs®, Fab derivatives) including BMS-936559, TMB-360 and those    targeting HIV gp120 or gp41 selected from the group consisting of    bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10,    3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2,    10E8 and VRC07, as well as HIV antibodies such as VRC-07-523;-   (17) latency reversing agents selected from the group consisting of    Histone deacetylase inhibitors such as Romidepsin, vorinostat,    panobinostat; Proteasome inhibitors such as Velcade; protein kinase    C (PKC) activators such as Indolactam, Prostratin, Ingenol B and    DAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15,    JQ1, disulfram, and amphotericin B;-   (18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group    consisting of azodicarbonamide;-   (19) HIV maturation inhibitors selected from the group consisting of    BMS-955176 and GSK-2838232;-   (20) PI3K inhibitors selected from the group consisting of    idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib,    rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib,    duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,    panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093,    pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,    RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib,    LY-3023414, SAR-260301 and CLR-1401;-   (21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO    2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO    2013/006738 (Gilead Sciences), US 2013/0165489 (University of    Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan    Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285    (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO    2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead    Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead    Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead    Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498    (Gilead Sciences); and-   (22) other drugs for treating HIV selected from the group consisting    of BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107,    alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan,    Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN,    VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43,    MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide,    ABX-464, SCY-635, naltrexone and PA-1050040 (PA-040); and other    drugs for treating HIV selected from AAV-eCD4-Ig gene therapy,    TEV-90110, TEV-90112, TEV-90111, TEV-90113, deferiprone, and    HS-10234.

In certain embodiments, the additional therapeutic agent is a compounddisclosed in US 2014-0221356 (Gilead Sciences, Inc.) for example(2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,and(1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide, US2015-0018298 (Gilead Sciences, Inc.)and US2015-0018359 (Gilead Sciences, Inc.),

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In a specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In a further embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith an HIV nucleoside or nucleotide inhibitor of reverse transcriptase,an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIVprotease inhibiting compound. In an additional embodiment, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is combined with an HIV nucleoside or nucleotide inhibitor of reversetranscriptase, an HIV non-nucleoside inhibitor of reverse transcriptase,and a pharmacokinetic enhancer. In certain embodiments, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is combined with one or more additional therapeutic agents selected fromHIV nucleoside inhibitor of reverse transcriptase, an integraseinhibitor, and a pharmacokinetic enhancer. In another embodiment, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two HIV nucleoside or nucleotideinhibitors of reverse transcriptase.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from Triumeq®(dolutegravir+abacavir+lamivudine), dolutegravir+abacavirsulfate+lamivudine, raltegravir, Truvada® (tenofovir disoproxilfumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom®(Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovirdipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride,Complera® (Eviplera®, rilpivirine+tenofovir disoproxilfumarate+emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovirdisoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate,dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir),ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir,lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz,Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir,amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol),Hlviral, lamivudine+tenofovir disoproxil fumarate,efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid,lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide and tenofovir alafenamide hemifumarate. In certainembodiments, the one, two, three, four or more additional therapeuticagents are further selected from raltegravir+lamivudine, atazanavirsulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat,darunavir+cobicistat, atazanavir sulfate+cobicistat,atazanavir+cobicistat.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from Triumeq®(dolutegravir+abacavir+lamivudine), dolutegravir+abacavirsulfate+lamivudine, raltegravir, Truvada® (tenofovir disoproxilfumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom®(Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovirdipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride,Complera® (Eviplera®, rilpivirine+tenofovir disoproxilfumarate+emtricitabine), cobicistat, Atripla® (efavirenz+tenofovirdisoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate,dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir),ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir,lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz,Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir,amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol),Hlviral, lamivudine+tenofovir disoproxil fumarate,efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid,lamivudine+nevirapine+zidovudine,(2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,and(1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamideabacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir alafenamide and tenofovir alafenamidehemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarateand a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30;15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 10 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 25 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mgemtricitabine. A compound of the present disclosure (e.g., a compound offormula (I)) may be combined with the agents provided herein in anydosage amount of the compound (e.g., from 1 mg to 500 mg of compound)the same as if each combination of dosages were specifically andindividually listed.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 200-250; 200-300; 200-350; 250-350;250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mgemtricitabine. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 300 mg tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. Acompound of the present disclosure (e.g., a compound of formula (I)) maybe combined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed. Acompound of the present disclosure (e.g., a compound of Formula (I)) maybe combined with the agents provided herein in any dosage amount of thecompound (e.g. from about 1 mg to about 150 mg of compound) the same asif each combination of dosages were specifically and individuallylisted.

In certain embodiments a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with(2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,l1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,or(1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide.

Also provided herein is a compound the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating HIV, for usein a method of treating or preventing HIV.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HIV, wherein the compoundor a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with one or more additionaltherapeutic agents for treating HIV.

In certain embodiments, a method for treating hyperproliferativedisorders such as cancer in a human is provided, comprisingadministering to the human a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more (e.g., one, two, three, one or two, or one to three)additional therapeutic agents. In one embodiment, a method for treatinghyperproliferative disorders such as cancer in a human is provided,comprising administering to the human a therapeutically effective amountof a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents.

X. COMBINATION THERAPY FOR CANCER

In certain embodiments, the present disclosure provides a method fortreating hyperproliferative disorders such as cancer, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of the present disclosure, or a pharmaceuticallyacceptable salt, thereof, in combination with a therapeuticallyeffective amount of one or more additional therapeutic agents which aresuitable for treating hyperproliferative disorders such as cancer.

In the above embodiments, the additional therapeutic agent may be ananti-cancer agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting ofchemotherapeutic agents, immunotherapeutic agents, radiotherapeuticagents, anti-neoplastic agents, anti-hormonal agents, anti-angiogenicagents, anti-fibrotic agents, therapeutic antibodies, tyrosine kinaseinhibitors, JAK inhibitors, Hedgehog inhibitors, HDAC inhibitors,Discoidin domain receptor (DDR) inhibitors, MMP9 inhibitors, LOXLinhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYKinhibitors, mTOR inhibitors, AKT inhibitors, Mitogen or ExtracellularRegulated Kinase (MEK) inhibitors, blockers of Raf kinases (rafk), CDKinhibitors, JNK inhibitors, MAPK inhibitors, Raf inhibitors, ROCKinhibitors, Tie2 inhibitors, Myo-inositol signaling inhibitors,phospholipase C blockers, anti-CD19 antibodies, anti-CD20 antibodies,anti-MN-14 antibodies, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74antibodies, cancer vaccines based upon the genetic makeup of anindividual patient's tumor, IDH1 inhibitors, BRD4 inhibitors, TPL2inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCRinhibitors, agents inhibiting the RAS/RAF/ERK pathway, protein kinase C(PKC) modulators, modulators of growth factor receptors such asepidermal growth factor receptor (EGFr), platelet derived growth factorreceptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factorreceptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermalgrowth factor homology domains (TIE-2), insulin growth factor-I (IGFI)receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet,fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, andTrkC), ephrin (eph) receptors, and the RET protooncogene, modulators oftyrosine kinases including cSrc, Lck, Fyn, Yes, cAbl, FAK (Focaladhesion kinase) and Bcr-Abl, modulators of PKB family kinases,modulators of TGF beta receptor kinases, inhibitors of Ras oncogeneincluding inhibitors of famesyltransferase, geranyl-geranyl transferase,and CAAX proteases, anti-sense oligonucleotides, ribozymes, Bcl-2 familyprotein inhibitors, proteasome inhibitors, Heat shock protein HSP90inhibitors, combination drugs and immunotherapy, and other drugs fortreating hyperproliferative disorders such as cancer, and combinationsthereof.

In certain embodiments a compound of the present disclosure isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating cancer. In certain embodiments, the tabletcan contain another active ingredient for treating cancer, such aschemotherapeutic agents, immunotherapeutic agents, radiotherapeuticagents, anti-neoplastic agents, anti-fibrotic agents, anti-hormonalagents, anti-angiogenic agents, Tyrosine kinase inhibitors, JAKinhibitors, Hedgehog inhibitors, HDAC inhibitors, Discoidin domainreceptor (DDR) inhibitors, MMP9 inhibitors, LOXL inhibitors, ASK1inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTORinhibitors, AKT inhibitors, Mitogen or Extracellular Regulated Kinase(MEK) inhibitors, blockers of Raf kinases (rafk), CDK inhibitors, JNKinhibitors, MAPK inhibitors, Raf inhibitors, ROCK inhibitors, Tie2inhibitors, Myo-inositol signaling inhibitors, phospholipase C blockers,IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1inhibitors; IKK inhibitors; BCR inhibitors, agents inhibiting theRAS/RAF/ERK pathway, protein kinase C (PKC) modulators, modulators ofgrowth factor receptors such as epidermal growth factor receptor (EGFr),platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret,vascular endothelial growth factor receptor (VEGFr), tyrosine kinasewith immunoglobulin-like and epidermal growth factor homology domains(TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colonystimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor(FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph)receptors, and the RET protooncogene, modulators of tyrosine kinasesincluding cSrc, Lck, Fyn, Yes, cAbl, FAK (Focal adhesion kinase) andBcr-Abl, modulators of PKB family kinases, modulators of TGF betareceptor kinases, inhibitors of Ras oncogene including inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases,anti-sense oligonucleotides, ribozymes, Bcl-2 family protein inhibitors,proteasome inhibitors, Heat shock protein HSP90 inhibitors, combinationdrugs and immunotherapy, and other drugs for treating hyperproliferativedisorders such as cancer, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Chemotherapeutic agents selected from the group consisting of:    anti-metabolites/anti-cancer agents, such as pyrimidine analogs    (floxuridine, capecitabine, and cytarabine); purine analogs, folate    antagonists and related inhibitors, antiproliferative/antimitotic    agents including natural products such as vinca alkaloid    (vinblastine, vincristine) and microtubule such as taxane    (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and    navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA    damaging agents (actinomycin, amsacrine, busulfan, carboplatin,    chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin,    daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan,    merchlorehtamine, mitomycin, mitoxantrone, nitrosourea,    procarbazine, taxol, taxotere, teniposide, etoposide,    triethylenethiophosphoramide); antibiotics such as dactinomycin    (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin,    anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin)    and mitomycin; enzymes (L-asparaginase which systemically    metabolizes L-asparagine and deprives cells which do not have the    capacity to synthesize their own asparagine); antiplatelet agents;    antiproliferative/antimitotic alkylating agents such as nitrogen    mustards cyclophosphamide and analogs, melphalan, chlorambucil), and    (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and    analogs, streptozocin, trazenes-dacarbazinine (DTIC);    antiproliferative/antimitotic antimetabolites such as folic acid    analogs (methotrexate); platinum coordination complexes (cisplatin,    oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,    aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,    goserelin, bicalutamide, nilutamide) and aromatase inhibitors    (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin    salts and other inhibitors of thrombin); fibrinolytic agents (such    as tissue plasminogen activator, streptokinase and urokinase),    aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory    agents; antisecretory agents (breveldin); immunosuppressives    tacrolimus, sirolimus azathioprine, mycophenolate; compounds    (TNP-470, genistein) and growth factor inhibitors (vascular    endothelial growth factor inhibitors, fibroblast growth factor    inhibitors); angiotensin receptor blocker, nitric oxide donors;    anti-sense oligonucleotides; cell cycle inhibitors and    differentiation inducers (tretinoin); inhibitors, topoisomerase    inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin,    eniposide, epirubicin, idarubicin, irinotecan and mitoxantrone,    topotecan, irinotecan), corticosteroids (cortisone, dexamethasone,    hydrocortisone, methylpednisolone, prednisone, and prednisolone);    growth factor signal transduction kinase inhibitors; dysfunction    inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,    Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin,    and caspase activators, chromatin, alkylating agents such as    thiotepa and cyclophosphamide (Cytoxan, Endoxan, Endoxana,    Cyclostin), alkyl sulfonates such as busulfan, improsulfan and    piposulfan; aziridines such as benzodopa, carboquone, meturedopa,    and uredopa; emylerumines and memylamelamines including alfretamine,    triemylenemelamine, triethylenephosphoramide,    triethylenethiophosphoramide and trimemylolomelamine; acetogenins    (especially bullatacin and bullatacinone); a camptothecin (including    synthetic analogue topotecan); bryostatin; callystatin; CC-1065    (including its adozelesin, carzelesin and bizelesin synthetic    analogues); cryptophycins (articularly cryptophycin 1 and    cryptophycin 8); dolastatin; duocarmycin (including the synthetic    analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a    sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,    chlomaphazine, cholophosphamide, estramustine, ifosfamide,    mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,    novembichin, phenesterine, prednimustine, trofosfamide, uracil    mustard; nitrosoureas such as carmustine, chlorozotocin,    foremustine, lomustine, nimustine, ranimustine; antibiotics such as    the enediyne antibiotics (e.g., calicheamicin, especially    calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew,    Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including    dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as    well as neocarzinostatin chromophore and related chromoprotein    enediyne antibiotic chromomophores), aclacinomysins, actinomycin,    authramycin, azaserine, bleomycins, cactinomycin, carabicin,    carrninomycin, carzinophilin, chromomycins, dactinomycin,    daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin    (including morpholino-doxorubicin, cyanomorpholino-doxorubicin,    2-pyrrolino-doxorubicin, PEGylated liposomal doxorubicin and    deoxydoxorubicin), epirubicin, esorubicin, idarubicin,    marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,    nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,    quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,    ubenimex, zinostatin, zorubicin; anti-metabolites such as    methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as    demopterin, methotrexate, pteropterin, trimetrexate; purine analogs    such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;    pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine,    carmofur, dideoxyuridine, doxifluridine, enocitabine, floxuridine;    androgens such as calusterone, dromostanolone propionate,    epitiostanol, mepitiostane, testolactone; anti-adrenals such as    aminoglutethimide, mitotane, trilostane; folic acid replinisher such    as frolinic acid; aceglatone; aldophosphamide glycoside;    aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene;    edatraxate; defofamine; demecolcine; diaziquone; elformthine;    elliptinium acetate; an epothilone; etoglucid; gallium nitrate;    hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as    maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol;    nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone;    fluoropyrimidine; folinic acid; podophyllinic acid;    2-ethylhydrazide; procarbazine; PSK(r); razoxane; rhizoxin;    sizofiran; spirogermanium; tenuazonic acid; triaziquone;    2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,    verracurin A, roridin A and anguidine); urethane; vindesine;    dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;    gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta;    taxoids, paclitaxel (Taxol) and docetaxel (Taxotere); chlorambucil;    gemcitabine (Gemzar); 6-thioguanine; mercaptopurine; methotrexate;    platinum analogs such as cisplatin and carboplatin; platinum;    ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine);    novantrone; teniposide; edatrexate; daunomycin; aminopterin;    xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;    difluoromethylomithine (DMFO); retinoids such as retinoic acid;    capecitabine and FOLFIRI (fluorouracil, leucovorin, and irinotecan);-   (2) Anti-hormonal agents selected from the group consisting of:    anti-estrogens and selective estrogen receptor modulators (SERMs),    including, for example, tamoxifen (including Nolvadex), raloxifene,    droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,    onapristone, and toremifene; inhibitors of the enzyme aromatase,    which regulates estrogen production in the adrenal glands, such as,    for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate,    exemestane, formestane, fadrozole, vorozole, letrozole and    anastrozole, and anti-androgens such as flutamide, nilutamide,    bicalutamide, leuprolide, and goserelin;-   (3) Anti-angiogenic agents selected from the group consisting of:    retinoid acid and derivatives thereof, 2-methoxyestradiol,    ANGIOSTATIN, ENDOSTATIN, suramin, squalamine, tissue inhibitors of    metalloproteinase-1, tissue inhibitors of metalloproteinase-2,    plasminogen activator inhibitor-1, plasminogen activator    inbibitor-2, cartilage-derived inhibitors, paclitaxel    (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine),    sulphated chitin derivatives (prepared from queen crab shells),    sulphated polysaccharide peptidoglycan complex (sp-pg),    staurosporine, modulators of matrix metabolism, including for    example, proline analogs ((1-azetidine-2-carboxylic acid (LACA),    cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,    .alpha.-dipyridyl, beta-aminopropionitrile fumarate,    4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate,    mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,    chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin;    fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),    beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene,    lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid    disodium or “CCA”, thalidomide; angiostatic steroid,    cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94,    antibodies, preferably monoclonal antibodies against these    angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF    isoforms, VEGF-C, HGF/SF, Ang-1/Ang-2 and the compounds disclosed in    Ferrara N. and Alitalo, K. “Clinical application of angiogenic    growth factors and their inhibitors” (1999) Nature Medicine    5:1359-1364;-   (4) Anti-fibrotic agents selected from the group consisting of:    beta-aminoproprionitrile (BAPN), primary amines reacting with the    carbonyl group of the active site of the lysyl oxidases, and more    particularly those which produce, after binding with the carbonyl, a    product stabilized by resonance, such as the following primary    amines: emylenemamine, hydrazine, phenylhydrazine, and their    derivatives, semicarbazide, and urea derivatives, aminonitriles,    such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine,    unsaturated or saturated haloamines, such as 2-bromo-ethylamine,    2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine,    p-halobenzylamines, selenohomocysteine lactone, copper chelating    agents, indirect inhibitors such as compounds blocking the aldehyde    derivatives originating from the oxidative deamination of the lysyl    and hydroxylysyl residues by the lysyl oxidases, such as the    thiolamines, in particular D-penicillamine, or its analogues such as    2-amino-5-mercapto-5-methylhexanoic acid,    D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,    p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,    sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane    sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate,    sodium-4-mercaptobutanesulphinate trihydrate, the compounds    disclosed in U.S. Pat. Nos. 4,965,288, 4,997,854, 4,943,593,    5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608 and U.S.    Patent Application No. 2004/0248871;-   (5) Therapeutic antibodies selected from the group consisting of:    abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab,    amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab,    bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab,    catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab,    conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab,    detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab,    ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab,    figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab,    girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab,    indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab,    labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab,    mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab,    moxetumomab, namatumab, naptumomab, necitumumab, nimotuzumab,    nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,    oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab,    pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,    radretumab, rilotumumab, rituximab, robatumumab, satumomab,    sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab,    taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab,    trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab,    votumumab, zalutumumab, alemtuzumab, veltuzumab, apolizumab,    bevacizumab, epratuzumab, tositumomab, galiximab, ibritumomab,    lumiliximab, milatuzumab, obinutuzumab, ofatumumab, CC49 and 3F8,    wherein the antibody may be further labeled or combined with a    radioisotope particle, such as indium In 111, yttrium Y 90, iodine    I-131;-   (6); JAK inhibitors selected from the group consisting of:    ruxolitinib, fedratinib, tofacitinib, baricitinib, lestaurtinib,    pacritinib, momelotinib, XL019, AZD1480, INCB039110, LY2784544,    BMS911543, and NS018;-   (7) Hedgehog inhibitors selected from the group consisting of:    saridegib;-   (8) Histone deacetylase (HDAC) inhibitors selected from the group    consisting of: pracinostat, romidepsin, vorinostat and panobinostat;-   (9) Tyrosine kinase inhibitors selected from the group consisting    of: lestaurtinib, gefitinib, erlotinib and sunitinib;-   (10) Discoidin domain receptor (DDR) inhibitors selected from the    group consisting of: the inhibitors disclosed in US2009/0142345,    US2011/0287011, WO2013/027802, WO2013/034933, and U.S. Provisional    Application No. 61/705,044;-   (11) MMP9 inhibitors selected from the group consisting of:    marimastat (BB-2516), cipemastat (Ro 32-3555), and the inhibitors    described in WO2012/027721;-   (12) LOXL inhibitors selected from the group consisting of: the    antibodies described in WO2009/017833, the antibodies described in    WO2009/017833, WO2009/035791 and WO/2011/097513;-   (13) ASK1 inhibitors selected from the group consisting of: the    compounds described in WO2011/008709 and WO/2013/112741;-   (14) PI3K inhibitors selected from the group consisting of: the    compounds described in U.S. Pat. No. 7,932,260, U.S. Provisional    Application Nos. 61/543,176; 61/581,528; 61/745,429; 61/745,437; and    61/835,333, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414,    RP5090, KAR4141, XL499, OXY111A, duvelisib, IPI-443, GSK2636771, BAY    10824391, TGX221, RG-7666, CUDC-907, PQR-309, DS-7423, panulisib,    AZD-8186, CLR-457, pictilisib, neratinib, rigosertib, rigosertib    sodium, EN-3342, UCB-5857, taselisib, INCB-040093, pilaralisib,    BAY-1082439, puquitinib mesylate, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, alpelisib, buparlisib, BAY 80-6946, BYL719,    PX-866, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, RP-6530,    AS252424, LY294002, TG100115, LY294002, BEZ235, XL147 (SAR245408),    SAR-245409, GDC-0941, BKM120, CH5132799, XL756, MLN-1117, SF-1126,    RV-1729, sonolisib, GDC-0980, CLR-1401, perifosine and wortmannin;-   (15) BTK inhibitors selected from the group consisting of:    ibrutinib, HM71224, ONO-4059 and CC-292;-   (16) SYK inhibitors selected from the group consisting of: tamatinib    (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205 AA,    R112, R343, and the compounds described in U.S. Pat. No. 8,450,321;-   (17) mTOR inhibitors selected from the group consisting of:    temsirolimus, everolimus, ridaforolimus, deforolimus, OSI-027,    AZD2014, CC-223, RAD001, LY294002, BEZ235, rapamycin, Ku-0063794,    and PP242;-   (18) AKT inhibitors selected from the group consisting of:    perifosine, MK-2206, GDC-0068 and GSK795;-   (19) MEK inhibitors selected from the group consisting of:    trametinib, selumetinib, cobimetinib, MEK162, PD-325901, PD-035901,    AZD6244, and CI-1040;-   (20) CDK inhibitors selected from the group consisting of: AT-7519,    alvocidib, palbociclib and SNS-032;-   (21) JNK inhibitors selected from the group consisting of: CC-401;-   (22) MAPK inhibitors selected from the group consisting of: VX-702,    SB203580 and SB202190;-   (23) Raf inhibitors selected from the group consisting of: PLX4720;-   (24) ROCK inhibitors selected from the group consisting of: Rho-15;-   (25) Tie2 inhibitors selected from the group consisting of:    AMG-Tie2-1;-   (26) Myo-inositol signaling inhibitors such as phospholipase C    blockers and Myoinositol analogues described in Powis, G., and    Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy    ed., Paul Workman and David Kerr, CRC press 1994, London;-   (27) Bcl-2 family protein inhibitors selected from the group    consisting of: ABT-263, ABT-199 and ABT-737;-   (28) IKK inhibitors selected from the group consisting of:    BMS-345541;-   (29) Proteasome inhibitors selected from the group consisting of:    bortezomib;-   (30) Protein kinase C (PKC) inhibitors selected from the group    consisting of: bryostatin 1 and enzastaurin;-   (31) Heat shock protein HSP90 inhibitors selected from the group    consisting of: Geldanamycin;-   (32) Combination drugs selected from the group consisting of: FR    (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide,    rituximab), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus    CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), CHOP    (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP    (cyclophosphamide, vincristine and prednisone), FCM (fludarabine,    cyclophosphamide, mitoxantrone), hyperCVAD (hyperfractionated    cyclophosphamide, vincristine, doxorubicin, dexamethasone,    methotrexate, cytarabine), ICE (iphosphamide, carboplatin and    etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), and    R MCP (R MCP); and-   (33) other drugs for treating cancer selected from the group    consisting of aldesleukin, alvocidib, CHIR-12.12, ha20, tiuxetan,    PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide    vaccine, autologous human tumor-derived HSPPC-96, GTOP-99 (MyVax®),    antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin,    beta alethine, arsenic trioxide, amifostine, aminocamptothecin,    lenalidomide, caspofungin, clofarabine, ixabepilone, cladribine,    chlorambucil, Curcumin, vinorelbine, tipifamib, tanespimycin,    sildenafil citrate, denileukin diftitox, simvastatin, epoetin alfa,    fenretinide, filgrastim, mesna, mitoxantrone, lenalidomide,    fludarabine, mycophenolate mofetil, nelarabine, octreotide,    oxaliplatin, pegfilgrastim, recombinant interleukin-12, recombinant    interleukin-11, recombinant flt3 ligand, recombinant human    thrombopoietin, sargramostim, lymphokine-activated killer cells,    omega-3 fatty acids, recombinant interferon alfa, therapeutic    allogeneic lymphocytes and cyclosporine analogs.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected fromibrutinib, aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, ABT-263, ABT-199, ABT-737, BMS-345541,bortezomib, bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103,carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine(Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), denileukindiftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin(Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin,epoetin alfa, etoposide, everolimus (RAD001), fenretinide, filgrastim,melphalan, mesna, flavopiridol, fludarabine (Fludara), Geldanamycin (17AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide(Revlimid®), lymphokine-activated killer cells, melphalan, methotrexate,mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil,nelarabine, oblimersen Obatoclax, oblimersen, octreotide acetate,omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylatedliposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent),perifosine, Prednisolone, Prednisone, selicilib, recombinant interferonalfa, recombinant interleukin-12, recombinant interleukin-11,recombinant flt3 ligand, recombinant human thrombopoietin, rituximab,sargramostim, sildenafil citrate, simvastatin, sirolimus, Styrylsulphones, tacrolimus, tanespimycin, temsirolimus, thalidomide,therapeutic allogeneic lymphocytes, thiotepa, tipifamib, Vincristine,vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA),vorinostat, FR (fludarabine, rituximab), CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone), CVP (cyclophosphamide,vincristine and prednisone), FCM (fludarabine, cyclophosphamide,mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatinand etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone),R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM(rituximab plus FCM), R-ICE (rituximab-ICE), and R MCP (R MCP).

Any of the methods of treatment provided may be used to treat cancer atvarious stages. By way of example, the cancer stage includes but is notlimited to early, advanced, locally advanced, remission, refractory,reoccurred after remission and progressive.

In addition, the subject may be a human who is undergoing one or morestandard therapies, such as chemotherapy, radiotherapy, immunotherapy,surgery, or combination thereof. Accordingly, one or more anti-canceragents may be administered before, during, or after administration ofchemotherapy, radiotherapy, immunotherapy, surgery or combinationthereof.

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine 1-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating cancer, foruse in a method of treating cancer.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating cancer, wherein the compound or apharmaceutically acceptable salt thereof is administered simultaneously,separately or sequentially with one or more additional therapeuticagents for treating cancer.

XI. KITS

The present disclosure provides a kit comprising a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof. Thekit may further comprise instructions for use, e.g., for use inmodulating a toll-like receptor (e.g. TLR-8), such as for use intreating a disease, disorder, or condition. In certain embodiments theuse is for treating a HIV, HBV, or HCV infection. In certain embodimentsthe use is for treating a HBV infection. The instructions for use aregenerally written instructions, although electronic storage media (e.g.,magnetic diskette or optical disk) containing instructions are alsoacceptable.

The present disclosure also provides a pharmaceutical kit comprising oneor more containers comprising a compound of the present disclosure or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice reflects approval by the agency for themanufacture, use or sale for human administration. Each component (ifthere is more than one component) can be packaged in separate containersor some components can be combined in one container wherecross-reactivity and shelf life permit. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

XII. COMPOUND PREPARATION

Also provided are articles of manufacture comprising a unit dosage of acompound of the present disclosure or a pharmaceutically acceptable saltthereof, in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.)

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography. See, e.g.,Introduction to Modem Liquid Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin LayerChromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

XIII. EXAMPLES

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formulas (I) or (J).

Representative syntheses of compounds of the present disclosure aredescribed in schemes below, and the particular examples that follow.

Scheme 1 shows a representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

In Scheme 1, compounds of formula A1 (where R¹, R², and R³ are asdefined herein or are suitably protected derivatives of R¹, R², and R³)are converted to the corresponding 4-amino,2-chloro heterocycle byreaction with a nuclephilic amine in the presence of a suitable base(such as DIPEA) at room temperature. The compound of formula A2 is thentreated with 2,4-dimethoxybenzylamine at elevated temperature resultingin a 2,4-diaminopyrimidine of formula A3. In cases where R¹, R², and R³is a diversifiable chemical group such as Cl or Br, further replacementof R¹, R², and R³ by a variety of methods including cyanation,nucleophilic aromatic displacement, and metal catalyzed cross couplingreactions such as Suzuki couplings is carried out to provide products offormula A4. Treatment with a suitable acid (such as trifluoroaceticacid) leads to certain compounds of Formula (I) or (J). Where suitable,other leaving groups may be used in place of the C1 group(s) of A1.

2,4-dichloro pyrido-pyrimidines of formula A1 (where R¹, R², and R³ areas defined herein or are suitably protected derivatives of R¹, R², andR³) are converted to the corresponding 4-amino,2-chloro heterocycle byreaction with an amino acid ester (such as L-norvaline methyl ester) inthe presence of a suitable base (such as DIPEA) at room temperature toprovide a compound of formula B1, where G is an the sidechain of theamino acid. The compound of formula B1 is then treated with2,4-dimethoxybenzylamine in a microwave reactor at a suitabletemperature (such as about 135° C.), resulting in a2,4-diaminopyrimidine of formula B2. Hydrolysis of the ester group viatreatment with a suitable base (such as aqueous KOH/THF) providesproduct of formula B3 where Z is hydroxyl. Further reaction of theresulting carboxylic acid leads to modification of Z via HATU-promotedamide formation with various amines. Protecting group removal with asuitable acid (such as trifluoroacetic acid) at room temperature thenleads to certain compounds of Formula (J) or (I).

Scheme 3 shows a representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

An amide of formula C1 (where R¹, R², and R³ are as defined herein orare suitably protected derivatives of R¹, R², and R³, and Z¹ is NH² orO-alkyl) is converted to a compound of formula C2, under suitablereaction conditions. For example, the compound of formula C1 iscontacted with chloroformamidine hydrochloride under suitable conditionsto provide C2. The hydroxyl group may be further modified, for exampleby introducing any suitable leaving group, such as a tosyl group, priorto contacting with R⁴—NH₂. Alternatively, R⁴—NH₂ may be directly coupledto C2 im the presence of a suitable coupling agent, for example, BOPreagent, under suitable conditions.

Additionally, a compound of Formula A1 (where R¹, R², and R³ are asdefined herein or are suitably protected derivatives of R¹, R², and R³)may be prepared as described in the scheme below. It is understood thatA1 may be further modified to prepare compounds of Formula (I) as morefully described herein.

As described above C1 is contacted with a suitable agent, such astriphosgene and dioxane, to result in a compound of D1. The compound D1may be further halogenated under suitable conditions, such as treatmentwith POCl₃ and PCl₅, to provide a compound of formula A1.

In certain instances, the above processes further involve the step offorming a salt of a compound of the present disclosure. Embodiments aredirected to the other processes described herein; and to the productprepared by any of the processes described herein.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, 5^(th) edition, NewYork: Oxford University Press, 2009; Smith, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

The methods of the present invention generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordisatereomerically pure.

Example 1

Synthesis ofN⁴-butyl-N²-(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine-2,4-diamine(1A)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (CAS#39551-54-7,supplied by Astatech, Inc.) (50 mg, 0.25 mmol) in THF (2 mL) was addedbutan-1-amine (0.03 mL, 0.28 mmol) and N,N-diisopropylethylamine (0.13ml, 0.75 mmol). After stirring at room temperature for 30 minutes,2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) andN,N-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and themixture was heated to 100° C. After 16 hours, the reaction was cooled toroom temperature, diluted with ethyl acetate, washed with water andbrine, dried over Na2SO4, and concentrated in vacuo. The product (1A)was obtained after flash chromatography. MS (m/z): 368.14 [M+H]⁺.

Synthesis of N⁴-butylpyrido[3,2-d]pyrimidine-2,4-diamine (1B)

1A was dissolved in trifluoroacetic acid (3 mL). After 30 minutes, thereaction was diluted with water and methanol. After 60 minutes, themixture was concentrated in vacuo. The residue was then co-evaporatedwith methanol three times and filtered in methanol to afford the titleproduct 1B as a trifluoroacetic acid salt. ¹H NMR (400 MHz, Methanol-d₄)δ 8.59 (dd, J=4.4, 1.4 Hz, 1H), 7.82 (dd, J=8.5, 1.4 Hz, 1H), 7.72 (dd,J=8.5, 4.4 Hz, 1H), 3.66 (t, J=7.3 Hz, 2H), 1.78-1.62 (m, 2H), 1.43 (dq,J=14.7, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS (m/z): 218.10 [M+H]⁺.¹⁹F NMR (377 MHz, Methanol-d4) δ −77.6.

Example 2

Synthesis ofN²-(2,4-dimethoxybenzyl)-N⁴-(pentan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine(2A)

2A was synthesized following the procedure described above forpreparation of 1A, replacing butan-1-amine with 2-aminopentane. MS (m/z)382.17 [M+H]⁺.

Synthesis of N⁴-(pentan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (2B)

2B was prepared following the procedure described for 1B to yield thetitle compound (2B) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ8.61 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.74 (dd,J=8.5, 4.4 Hz, 1H), 4.60-4.46 (m, 1H), 1.74 (dtd, J=13.5, 8.3, 6.7 Hz,1H), 1.68-1.55 (m, 1H), 1.44 (d, J=7.4 Hz, 2H), 1.32 (d, J=6.6 Hz, 3H),0.95 (t, J=7.4 Hz, 3H). MS (m/z) 232.11 [M+H]⁺. 19F NMR (377 MHz,Methanol-d4) δ −77.5.

Synthesis of(S)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4-methylpentan-1-ol(3A)

3A was synthesized following the above procedure for 1A, replacingbutan-1-amine with (S)-(+)-leucinol. MS (m/z) 412.19 [M+H]⁺.

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4-methylpentan-1-ol(3B)

3B was synthesized using the procedure described above for thepreparation of 1B to yield the title compound (3B) as its TFA salt. ¹HNMR (400 MHz, Methanol-d4) δ 8.62 (dd, J=4.4, 1.3 Hz, 1H), 7.84 (dd,J=8.5, 1.4 Hz, 1H), 7.74 (dd, J=8.5, 4.4 Hz, 1H), 4.74-4.58 (m, 1H),3.71 (h, J=6.2 Hz, 2H), 1.76-1.58 (m, 2H), 1.52 (tq, J=10.6, 3.5 Hz,1H), 0.98 (t, J=6.4 Hz, 6H). MS (m/z) 262.15 [M+H]⁺. ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.6

Example 4

Synthesis of(S)-3-cyclopropyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)propan-1-ol(4A)

4A was prepared using the procedure described above for the preparationof 1A, replacing butan-1-amine with(2S)-2-amino-3-cyclopropylpropan-1-ol HCl salt. MS (m/z) 410.20 [M+H]⁺

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-cyclopropylpropan-1-ol(4B)

4B was synthesized following the procedure described above for 1B toyield the title compound (4B) as its TFA salt. ¹H NMR (400 MHz,Methanol-d₄) δ 8.62 (dd, J=4.4, 1.3 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz,1H), 7.75 (dd, J=8.5, 4.4 Hz, 1H), 4.63 (dq, J=7.3, 5.5 Hz, 1H), 3.81(d, J=5.2 Hz, 2H), 1.65 (h, J=7.1 Hz, 2H), 0.78 (dddd, J=15.0, 10.1,5.1, 2.1 Hz, 1H), 0.45 (dddd, J=11.1, 9.4, 7.9, 4.6 Hz, 2H), 0.19-0.07(m, 2H). MS (m/z) 260.15 [M+H]⁺. ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.6

Example 5

Synthesis of (S)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentanoate(5A)

5A was prepared following the general procedure described above for 1A,replacing butan-1-amine with (S)-methyl 2-aminopentanoate. MS (m/z)426.19 [M+H]⁺.

Synthesis of (S)-methyl2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanoate (5B)

5B was prepared following the procedure described above for lB to yieldthe title compound (5B) as its TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ8.66 (dd, J=4.4, 1.4 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.79 (dd,J=8.5, 4.4 Hz, 1H), 5.02 (dd, J=8.7, 5.3 Hz, 1H), 3.78 (s, 3H),2.13-1.92 (m, 2H), 1.56-1.39 (m, 2H), 0.99 (t, J=7.4 Hz, 3H). MS (m/z)276.13 [M+H]⁺. ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.8.

Example 6

Synthesis of(S)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(6A)

6A was prepared following the procedure described above for 1A,replacing butan-1-amine with (S)-methyl 2-aminopentanoate and insteadstarting from 2,4,8-trichloro-6-methylpyrido[3,2-d]pyrimidine in placeof 2,4-dichloropyrido[3,2-d]pyrimidine. MS (m/z) 446.20 [M+H]⁺.

Synthesis of(S)-2-((2-amino-8-chloro-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(6B)

6B was prepared following the procedure described above for 1B to yieldthe title compound (6B) as its TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ7.84 (s, 1H), 4.55 (ddd, J=12.6, 7.2, 5.2 Hz, 1H), 3.75 (d, J=5.3 Hz,3H), 1.79-1.67 (m, 3H), 1.51-1.35 (m, 3H), 0.98 (t, J=7.4 Hz, 4H). MS(m/z) 296.18 [M+H]⁺. ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.6.

Example 7

Compound 7,(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-phenylethanol, wasprepared following the procedure for compound 1B reported above, insteadreplacing butan-1-amine with (S)-2-amino-2-phenylethanol to yield thetitle compound (7) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.68(dd, J=4.3, 1.5 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.77 (dd, J=8.5,4.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.24 (m, 1H),5.57 (dd, J=7.4, 4.8 Hz, 1H), 4.12-3.93 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.7. MS (m/z) 282.1 [M+H]⁺.

Example 8

Compound 8,(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol, wasprepared following the procedure for the synthesis of compound 1Breported above, instead replacing butan-1-amine with(R)-2-aminopentan-1-ol to yield the title compound (8) as its TFA salt.¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd,J=8.5, 1.5 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.55 (dq, J=7.4, 5.4Hz, 1H), 3.78-3.69 (m, 2H), 1.77-1.65 (m, 2H), 1.52-1.36 (m, 2H), 0.98(t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.56. MS (m/z)248.1 [M+H]⁺.

Example 9

Compound 9,(2S,3S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylpentan-1-ol,was prepared following the procedure for compound 1B reported above,instead replacing butan-1-amine with (2S,3S)-2-amino-3-methylpentan-1-olto yield the title compound (9) as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz,1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.39 (dt, J=8.1, 5.0 Hz, 1H), 3.83(d, J=5.0 Hz, 2H), 1.97-1.82 (m, 1H), 1.58 (dddd, J=16.8, 11.2, 7.6, 3.8Hz, 1H), 1.33-1.16 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.94 (t, J=7.4 Hz,3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.71. MS (m/z) 262.1 [M+H]⁺.

Example 10

Compound 10,(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4-(methylthio)butan-1-ol,was prepared following the 2 step procedure for compound 1B reportedabove, replacing butan-1-amine with (S)-2-amino-4-(methylthio)butan-1-olto yield the title compound (10) as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 1.4 Hz,1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.66 (dq, J=8.1, 5.4 Hz, 1H), 3.76(d, J=5.3 Hz, 2H), 2.65-2.52 (m, 2H), 2.11-1.98 (m, 5H). ¹⁹F NMR (376MHz, Methanol-d4) δ −77.63. MS (m/z) 280.1 [M+H]⁺.

Example 11

Compound 11, N⁴-pentylpyrido[3,2-d]pyrimidine-2,4-diamine, was preparedfollowing the procedure for compound 1B reported above, insteadreplacing butan-1-amine with n-pentylamine to yield the title compound(11) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.62 (dd, J=4.4,1.4 Hz, 1H), 7.81 (dd, J=8.5, 1.4 Hz, 1H), 7.74 (dd, J=8.5, 4.4 Hz, 1H),3.67 (dd, J=7.8, 6.8 Hz, 2H), 1.80-1.66 (m, 2H), 1.49-1.32 (m, 4H),0.99-0.85 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.58. MS (m/z)232.1 [M+H]⁺.

Example 12

Compound 12, 2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethanol, wasprepared following the procedure for compound 1B reported above, insteadreplacing butan-1-amine with ethanolamine to yield the title compound(12) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dd, J=4.3,1.5 Hz, 1H), 7.88-7.72 (m, 2H), 3.82 (d, J=2.3 Hz, 4H). ¹⁹F NMR (376MHz, Methanol-d4) δ −77.58. MS (m/z) 206.0 [M+H]⁺.

Example 13

Compound 13, 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)propan-1-ol,was prepared following the 2 step procedure for compound 1B reportedabove, instead replacing butan-1-amine with propanolamine to yield thetitle compound (13) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ8.62 (td, J=4.6, 1.4 Hz, 1H), 7.87-7.70 (m, 2H), 3.80 (dt, J=11.7, 6.8Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 2.00-1.88 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.58. MS (m/z) 220.1 [M+H]⁺.

Example 14

Compound 14,(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, wasprepared following the procedure for compound 1B reported above, insteadreplacing butan-1-amine with (S)-2-aminohexan-1-ol to yield the titlecompound (14) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.63 (dd,J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5, 4.4Hz, 1H), 4.53 (dq, J=8.6, 5.4 Hz, 1H), 3.79-3.68 (m, 2H), 1.87-1.61 (m,2H), 1.52-1.31 (m, 4H), 1.01-0.85 (m, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.63. MS (m/z) 262.2 [M+H]⁺.

Example 15

Compound 15,(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, wasprepared following the procedure for compound 1B reported above, insteadreplacing butan-1-amine with (R)-2-aminohexan-1-ol to yield the titlecompound (15) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.66-8.59(m, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.77 (td, J=8.8, 4.4 Hz, 1H),4.59-4.42 (m, 1H), 3.81-3.68 (m, 2H), 1.90-1.65 (m, 2H), 1.49-1.35 (m,4H), 1.03-0.82 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.60. MS(m/z) 262.2 [M+H]⁺.

Example 16

Compound 16,N⁴-((tetrahydrofuran-2-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-diamine,was prepared following the procedure for compound 1B reported above,instead replacing butan-1-amine with (tetrahydrofuran-2-yl)-methanamineto yield the title compound (16) as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 1.4 Hz,1H), 7.75 (dd, J=8.5, 4.4 Hz, 1H), 4.24 (qd, J=6.8, 4.8 Hz, 1H), 3.93(dt, J=8.3, 6.5 Hz, 1H), 3.84-3.68 (m, 3H), 2.16-1.82 (m, 3H), 1.71(ddt, J=11.6, 8.0, 6.5 Hz, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.50.MS (m/z) 246.1 [M+H]⁺.

Example 17

Compound 17,2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)propane-1,3-diol, wasprepared following the procedure for compound 1B reported above, insteadreplacing butan-1-amine with 2-aminopropane-1,3-diol to yield the titlecompound (17) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dd,J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H), 7.77 (dd, J=8.5, 4.4Hz, 1H), 4.54 (p, J=5.5 Hz, 1H), 3.84 (d, J=5.5 Hz, 4H). ¹⁹F NMR (376MHz, Methanol-d4) δ −77.66. MS (m/z) 236.1 [M+H]⁺.

Example 18

Synthesis of 3-amino-5-bromopicolinamide (18B)

To a solution of 3-amino-5-bromopicolinic acid 18A (300 mg, 1.38 mmol, 1equiv.) in DMF (11 ml, 0.1 M) was added HATU (598 mg, 1.57 mmol, 1.1equiv.) followed by DIPEA (0.48 mL, 2.76 mmol, 2 equiv.) and ammoniumhydroxide (0.8 mL, 5.55 mmol, 4 equiv.). The mixture was allowed to stirovernight. Water (50 mL) was added and the mixture then extracted withEtOAc (3 times). The organic layer was separated, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The product (18B) wasobtained after flash chromatography. MS (m/z): 216.8 [M+H]⁺

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (18C)

To a flask containing 3-amino-5-bromopicolinamide (18B) (205 mg, 0.1mmol, 1 equiv.) was added chloroformamadine hydrochloride (140 mg, 1.3equiv.). The mixture was heated to 165° C. overnight. It was allowed tocool to room temperature, then filtered and washed with water and ethylether. The residue was allowed to air dry to furnish2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (1C) which was used withoutfurther purification. MS (m/z): 239.9 [M+H]⁺

Synthesis of N-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide(18D)

To a flask containing 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (1C)(155 mg, 0.64 mmol, 1 equiv.) was added acetic anhydride (3 mL). Themixture was heated to 115° C. for 4 hrs. It was concentrated underreduced pressure. It was filtered and washed with diethyl ether andhexane and allowed to air dry to obtainN-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide (18D). MS(m/z): 282.9 [M+H].⁺

Synthesis of N-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide(18E)

Into a solution ofN-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide (18D) (200 mg,0.71 mmol, 1 equiv.) was added acetonitrile (2 ml) and POCl₃ (1 ml)followed by DIPEA (0.12 mL, 0.71 mmol., 1 equiv.). The mixture wasrefluxed for 6 hours. The mixture was concentrated under reducedpressure. To it was added water (20 mL) then extracted with EtOAc (3times). The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title productN-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide (18E). MS(m/z): 298.9 [M+H].

Synthesis of(S)-2-((2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(18F)

To a solution ofN-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide (18E) (215 mg,0.71 mmol, 1 equiv.) was added DMF (1.5 ml) followed by DIPEA (0.38 mL,2.1 mmol, 3 equiv.) and (S)-(+)-2-Amino-1-pentanol (55 mg, 3.6 mmol, 5equiv.). The reaction was allowed to stir overnight. It was concentratedunder reduced pressure and purified by reverse phase HPLC to furnish thetitle compound (18F) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ8.41 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 4.34 (dd, J=8.5, 5.4 Hz,1H), 3.65-3.53 (m, 3H), 1.67-1.49 (m, 3H), 1.41-1.24 (m, 3H), 0.86 (t,J=7.4 Hz, 5H). ¹⁹F NMR (377 MHz, CD₃sOD) 6-77.52. MS (m/z): 368.2 [M+H].

Example 19

Synthesis of 2,4,7-trichloropyrido[3,2-d]pyrimidine (19B)

Into a microwave vial was added pyrido[3,2-d]pyrimidine-2,4-diol (19A)(200 mg, 1.2 mmol, 1 equiv.) is added POCl₃ (2.5 mL) and PCl₅ (1.53 g,7.4 mmol, 6 equiv.). The mixture was heated to 160° C. for 3 hr inmicrowave reactor. The reaction mixture was concentrated under reducedpressure and partitioned between EtOAc and H₂O. The organics wereseparated, dried, and removed in vacuo. The residue purified by columnchromatography on silica to provide the title compound. MS (m/z):236.6[M+H]⁺.

Synthesis of(S)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19C)

To a solution of 2,4,7-trichloropyrido[3,2-d]pyrimidine (19B) (160 mg,0.68 mmol, 1 equiv.) was added dioxane (4 ml) followed by DIPEA (0.18mL, 1.2 mmol, 1.5 equiv.) and (S)-(+)-2-Amino-1-pentanol (85 mg, 0.82mmol, 1.1 equiv.). The reaction was allowed to stir for an hr. It wasconcentrated under reduced pressure and used as is to provide the titlecompound. MS (m/z): 301.1[M+H]⁺.

Synthesis of(S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19D)

To a solution of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19C)(206 mg, 0.68 mmol, 1 equiv.) was added dioxane (4 ml) followed by DIPEA(0.24 mL, 1.4 mmol, 2 equiv.) and 2,4-demethoxybenzylamine (0.30 mL, 2.0mmol, 3 equiv.). The reaction was allowed heated at 120° C. overnight.The reaction mixture was partitioned between EtOAc and H₂O. The organicswere separated, dried, and removed in vacuo. The residue purified bycolumn chromatography on silica to provide the title compound. MS (m/z):432.2 [M+H].⁺

Synthesis of(S)-2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19E)

Into a solution of(S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19D) (35 mg, 0.08 mmol, 1 equiv.) was added DCM (2 mL) and TFA (0.5mL). After 3 hours the reaction mixture was concentrated under reducedpressure and purified by reverse phase HPLC to furnish the titlecompound (19E) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.48 (d,J=2.0 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 4.48 (dd, J=8.6, 5.3 Hz, 1H),3.93-3.74 (m, 2H), 3.71 (d, J=5.2 Hz, 3H), 1.77-1.57 (m, 2H), 1.50-1.36(m, 1H), 1.28 (s, 2H), 0.97 (t, J=7.4 Hz, 4H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.59 (d, J=80.2 Hz). MS (m/z): 282.1 [M+H].⁺

General Scheme for Examples 20-22

Example 20

Synthesis of(S)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19F)

Into a vial containing(S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19D) (25 mg, 0.06 mmol, 1 equiv.) was added methylboronic acid (8 mg,0.14 mmol, 2.5 equiv.), potassium phosphate tribasic (37 mg, 0.17 mmol,3 equiv.), palladium(0)-tetrakis(triphenylphosphine) (7 mg, 0.006 mmol,0.1 equiv.) along with dioxane (2 mL) and water (2 mL). The mixture isheated to 150° C. for 1 hr in a microwave reactor. The reaction mixturewas partitioned between EtOAc and H₂O. The organics were separated,dried, and removed in vacuo to furnish the title compound which was useddirectly. MS (m/z): 474.3 [M+H].⁺

Synthesis of(S)-2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(20)

Into the a flask containing 19F was added THF (2 mL), water (2 mL)followed by 2,3-dichloro-5,6-dicyanobenzoquinone (26 mg, 20.11 mmol, 2equiv.) After stirring overnight, the reaction mixture was partitionedbetween EtOAc and H₂O. The organics were separated, dried, and removedin vacuo. Purification was carried out using flash column chromatographyto furnish the title compound (20). ¹H NMR (400 MHz, Methanol-d4) δ 8.35(d, J=1.1 Hz, 1H), 7.49 (s, 1H), 4.54-4.34 (m, 1H), 3.70 (d, J=5.0 Hz,2H), 1.84-1.61 (m, 2H), 1.56-1.35 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS(m/z): 262.1 [M+H].⁺

Example 21

Synthesis of(S)-2-((2-amino-7-ethylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(21) was prepared according to the procedure used for 20, instead usingethylboronic acid in place of methylboronic acid. ¹H NMR (400 MHz,Methanol-d4) δ 8.65-8.30 (m, 1H), 7.62 (s, 1H), 4.61-4.38 (m, 1H),3.80-3.64 (m, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.71 (tdd, J=8.3, 6.5, 2.2Hz, 2H), 1.43 (dddd, J=12.4, 7.4, 5.1, 2.5 Hz, 2H), 1.39-1.23 (m, 4H),0.97 (t, J=7.3 Hz, 3H). MS (m/z): 276.2 [M+H]⁺.

Example 22

Synthesis of(S)-2-amino-4-((1-hydroxypentan-2-yl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile(22) was prepared according to the two step procedure used for 20,instead using Zn(CN)₂ in place of methylboronic acid. ¹H NMR (400 MHz,DMSO-d6) δ 7.93 (d, J=1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 2.95-2.68 (m,3H), 0.76 (d, J=7.3 Hz, 2H), 0.47 (d, J=7.6 Hz, 1H), 0.02 (t, J=7.4 Hz,4H). MS (m/z): 273.3 [M+H].

Example 23

Synthesis of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (23A)

To a solution of 2,4,7-trichloropyrido[3,2-d]pyrimidine (19B) (45 mg,0.19 mmol, 1 equiv.) was added dioxane (4 ml) followed by DIPEA (41 μL,0.23 mmol, 1.2 equiv.) and (R)-(−)-2-Amino-1-hexanol 97% (24.7 mg, 0.21mmol, 1.1 equiv.). The reaction was allowed to stir for an hr. It wasconcentrated under reduced pressure and used as is to provide the titlecompound. MS (m/z): 316.2[M+H].⁺

Synthesis of(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(23B)

To a solution of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (23A)(60 mg, 0.19 mmol, 1 equiv.) was added dioxane (4 ml) followed by DIPEA(68 μL, 0.38 mmol, 2 equiv.) and 2,4-demethoxybenzylamine (85 μL, 3.0mmol, 3 equiv.). The reaction was allowed heated at 120° C. overnight.The reaction mixture partitioned between EtOAc and H₂O. The organicswere separated, dried, and removed in vacuo. The residue purified bycolumn chromatography on silica to provide the title compound. MS (m/z):446.9 [M+H].⁺

Synthesis(R)-2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(23C)

To a solution of(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(20B) (50 mg, 0.11 mmol, 1 equiv.) was added DCM (2 mL) and TFA (0.5mL). After 3 hours the reaction mixture was concentrated under reducedpressure and purified by reverse phase HPLC to furnish the titlecompound (23C) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.60 (d,J=2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 4.58-4.44 (m, 1H), 3.79-3.63 (m,3H), 1.86-1.61 (m, 2H), 1.52-1.24 (m, 5H), 1.01-0.79 (m, 4H). ¹⁹F NMR(377 MHz, Methanol-d4) δ −77.61. MS (m/z): 296.2 [M+H].⁺

Example 24

Synthesis of methyl 3-amino-6-bromo-5-fluoropicolinate (24B)

To a solution of methyl 3-amino-5-fluoropicolinate (24A) (270 mg, 0.22mmol, 1 equiv.) was added acetonitrile (5 mL) and N-bromosuccinimide(310 mg, 0.24 mmol, 1.1 equiv.). The reaction was allowed to stir atroom temperature overnight. The reaction mixture partitioned betweenEtOAc and H₂O. The organics were separated, dried, and removed in vacuo.The residue purified by column chromatography on silica to provide thetitle compound. MS (m/z): 250.2 [M+H].⁺

Synthesis of 2-amino-6-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24C)

To a flask containing methyl 3-amino-6-bromo-5-fluoropicolinate (24B)(200 mg, 0.80 mmol, 1 equiv.) was added chloroformamadine hydrochloride(185 mg, 1.61 mmol, 2 equiv.). The mixture was heated to 165° C.overnight. It was allowed to cool down to room temperature it wasfiltered and washed with water and ethyl ether. The residue was allowedto air dry to provide the title compound (24C). Approximately, 25% ofthe product is the corresponding side product2-amino-6-bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol. The material wasused without further purification. MS (m/z): 260.0 [M+H].⁺

Synthesis of Synthesis of2-amino-6-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24D)

To a flask 2-amino-6-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24C)(50 mg, 0.23 mmol, 1 equiv.) is added(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate97% (BOP Reagent) (123 mg, 0.28 mmol, 10.2 equiv.),(S)-(+)-2-Amino-1-pentanol, 97% (48 mg, 0.47 mmol, 2 equiv.) and DBU(105 μL, 0.70 mmol, 3 equiv.) and DMF (3 mL). The mixture was allowed tostir at room temperature overnight and purified by reverse phase HPLC tofurnish the title compound (24D) as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 7.86-7.63 (m, 1H), 4.64-4.47 (m, 1H), 3.72 (d, J=5.5 Hz,2H), 1.82-1.61 (m, 3H), 1.56-1.35 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). ¹⁹FNMR (377 MHz, Methanol-d4) δ −77.54, −110.63 (d, J=8.2 Hz). MS (m/z):300.2 [M+H]⁺.

Example 25

Synthesis of N⁴-butyl-8-methylpyrido[3,2-d]pyrimidine-2,4-diamine (25E)

Beginning from intermediate 25A, treatment with 1.05 equiv butan-1-aminein THF/DIPEA at RT gave 25B, which was concentrated to a residue andcarried forward directly. Heating with excess 2,4-dimethoxybenzylaminein THF/DIPEA led to compound 25 C, with characteristic MS (m/z): 416.2[M+H].+Following the procedure reported by Hasnik et. al in Synthesis,2009, 1309-1317, instead of the expected 6-methylation via potassiummethyl trifluoroborate, protonolysis of the intermediate heteroaryl-Pdcomplex led mainly to isolation of 25D, and finally toN⁴-butyl-8-methylpyrido[3,2-d]pyrimidine-2,4-diamine 25E upon treatmentof 25D in excess TFA and final purification via HPLC to provide thetitle compound (25E) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ8.48 (d, J=1.1 Hz, 1H), 7.61 (d, J=1.1 Hz, 1H), 3.67 (d, J=7.2 Hz, 2H),2.52 (s, 3H), 1.75-1.68 (m, 2H), 1.46-1.35 (m, 2H), 0.98 (t, J=7.3 Hz,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.6. MS (m/z): 232.1 [M+H].⁺

Example 26

Synthesis of(S)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(26E)

Beginning from intermediate 25A and following the synthetic sequencereported above for the synthesis of 25E, but instead using L-norvalinolin place of butan-1-amine, 26E was obtained as its TFA salt. ¹H NMR (400MHz, Methanol-d4) δ 8.50 (d, J=4.6 Hz, 1H), 7.63 (dq, J=4.5, 0.8 Hz,1H), 4.60-4.49 (m, 1H), 3.78-3.70 (m, 2H), 2.53 (s, 3H), 1.81-1.64 (m,2H), 1.52-1.34 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.7. MS (m/z): 262.2 [M+H]⁺

Example 27

Synthesis of(S)-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (27C)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (160 mg, 0.68 mmol,1 equiv.) was added THF (4 ml) followed by DIPEA (0.18 mL, 1.2 mmol, 1.5equiv.) and (S)-(+)-2-amino-1-pentanol (85 mg, 0.82 mmol, 1.1 equiv.).The reaction was allowed to stir for 1h. The reaction was concentratedunder reduced pressure and used as is to provide 27A. MS (m/z):267.1[M+H].

Synthesis of(S)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(27B)

To a solution of(S)-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (27A) (206mg, 0.68 mmol, 1 equiv.) was added is added THF (4 ml) followed by DIPEA(0.24 mL, 1.4 mmol, 2 equiv.) and 2,4-dimethoxybenzylamine (0.30 mL, 2.0mmol, 3 equiv.). The reaction was heated at 135° C. via microwavereactor for 30 minutes. The reaction mixture was partitioned betweenEtOAc and H₂O. The organics were separated, dried, and removed in vacuo.The residue was purified by column chromatography on silica to provide27B. MS (m/z): 398.2 [M+H].⁺

Synthesis of (S)-2-((2-amino-[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(27C)

Into a solution of(S)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(27B) (35 mg, 0.08 mmol, 1 equiv.) was added DCM (2 mL) and TFA (0.5mL). After 3 hours the reaction mixture was concentrated under reducedpressure and purified by reverse phase HPLC to furnish the titlecompound (27C) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.65(dd, J=4.3, 1.5 Hz, 1H), 7.85-7.73 (m, 2H), 4.55 (s, 1H), 3.76-3.70 (m,2H), 1.77-1.66 (m, 2H), 1.44 (td, J=7.3, 4.2 Hz, 2H), 0.98 (t, J=7.4 Hz,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.6. MS (m/z): 248.2 [M+H]⁺

Example 28

Following the general procedure described above for the synthesis of 1B,2,4-dichloropyrido[3,2-d]pyrimidine was instead reacted with 1.1 equiv(S)-1,1,1-trifluoropentan-2-amine in place of 1-butan-amine and thencarried through the steps as reported above in Example 1 to provide(S)-N⁴-(1,1,1-trifluoropentan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine(28). ¹H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.67 (dd, J=4.4, 1.5 Hz,1H), 7.95-7.81 (m, 2H), 5.13 (t, J=8.9 Hz, 1H), 2.21-2.10 (m, 1H), 1.74(dd, J=12.1, 7.1 Hz, 1H), 1.44-1.36 (m, 1H), 1.27 (dq, J=13.7, 7.1 Hz,1H), 0.89 (t, J=7.3 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −73.9,−74.1. MS (m/z): 286.1 [M+H]⁺.

Example 29

Following the general procedure described above for the synthesis of 1B,2,4-dichloropyrido[3,2-d]pyrimidine was instead reacted with 1.1 equiv4,4,4-trifluorobutylamine in place of 1-butan-amine and then carriedthrough the steps as reported above for Example 1 to provideN⁴-(4,4,4-trifluorobutyl)pyrido[3,2-d]pyrimidine-2,4-diamine (29) afterHPLC purification as its TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 9.74 (t,J=6.0 Hz, 1H), 8.63 (dd, J=4.4, 1.4 Hz, 1H), 8.18-7.50 (m, 2H), 3.62 (q,J=6.7 Hz, 1H), 2.39-2.27 (m, 1H), 1.93-1.84 (m, 1H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −65.5, 75.6. MS (m/z): 272.1 [M+H]⁺

Example 30

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanamide (30B)

Beginning from 50 mg of the intermediate compound 5A previouslydescribed above, treatment with 1 equiv. aq. KOH in THF/MEOH (4 mL) for1h gave, upon removal of solvent, intermediate 30A, MS (m/z): 399.1[M+H]⁺. 30A was treated with 1.5 equiv HATU and 3 equiv DIPEA in 2 mLDMF, with quenching by excess 2,4-dimethoxybenzylamine (DMB) to providethe intermediate amide. After global DMB removal via TFA treatment, HPLCpurification of the product residue provided title compound 30B as itsTFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (ddd, J=9.2, 4.3, 1.5 Hz,1H), 7.89-7.73 (m, 2H), 4.00-3.59 (m, 1H), 2.81 (s, 2H), 2.22-1.79 (m,2H), 1.48 (tt, J=9.8, 7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377MHz, Methanol-d4) δ −77.6. MS (m/z): 261.1 [M+H]⁺.

Example 31

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-methylpentanamide(31)

50 mg of 30A was treated with 1.5 equiv HATU and 3 equiv DIPEA in 2 mLDMF, with quenching by 1.0 M methylamine in THF to provide theintermediate methylamide. After standard DMB removal via TFA treatment,HPLC purification of the product residue provided title compound 31 asits TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.68 (dd, J=4.3, 1.5 Hz,1H), 7.89-7.76 (m, 2H), 4.85 (m, 1H), 2.76 (s, 3H), 2.08-1.85 (m, 2H),1.45 (dddd, J=16.5, 13.8, 11.5, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). ¹⁹FNMR (377 MHz, Methanol-d4) δ −77.9. MS (m/z): 275.1 [M+H]⁺

Example 32

Synthesis ofN⁴-butyl-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine-2,4-diamine (32)

Beginning from 10 mg compound 1B, the synthesis of which is reported inExample 1, and proceeding with chemistry described by Yining et al. inPNAS, 2011, 108, 14411, 1B was heated at 55° C. in DMSO in the presenceof 10 equivalents of zinc trifluoromethane sulfinate and 10 equivt-butylhydroperoxide 70% aq. solution. After 24h, the reaction mixturewas injected directly onto HPLC for final purification to provide thetitle compound (32) as the corresponding TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.15 (d, J=8.7 Hz, 1H), 8.01 (dd, J=8.8, 0.8 Hz, 1H),3.82-3.56 (m, 2H), 1.83-1.61 (m, 2H), 1.58-1.31 (m, 2H), 0.99 (t, J=7.4Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ −69.0, −77.6. MS (m/z): 286.1[M+H]⁺.

Example 33

Synthesis of(S)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(33)

50 mg compound 6B, (0.11 mmol, 1 equiv) in 10 mL (1:1 EtOH/EtOAc) wasreacted with 28 mg 5% Pd/C at 70° C. under 1 atm H₂. After overnight,the reaction was filtered to remove catalyst and the productchromatographed on silica gel, eluting at 25% MeOH/75% EtOAc to providethe title compound (33) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ7.74 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 4.54 (ddd, J=12.4, 7.3,5.2 Hz, 1H), 3.75 (d, J=5.2 Hz, 2H), 2.65 (s, 3H), 1.73 (q, J=7.5 Hz,2H), 1.44 (ddt, J=14.6, 7.4, 4.2 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H). ¹⁹FNMR (377 MHz, Methanol-d4) δ −77.7. MS (m/z) 262.14 [M+H]⁺.

Example 34

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxyethyl)pentanamide(34)

The title compound was synthesized in a similar fashion to 30B asreported in Example 30, instead replacing methanolic ammonia withethanolamine to provide the title compound (34) as its TFA salt. ¹H NMR(400 MHz, Methanol-d4) δ 8.68 (dd, J=4.3, 1.5 Hz, 1H), 7.86 (dd, J=8.6,1.5 Hz, 1H), 7.80 (dd, J=8.5, 4.4 Hz, 1H), 4.88 (d, J=5.5 Hz, 1H),3.27-3.22 (m, 2H), 2.11-1.90 (m, 3H), 1.70-1.40 (m, 5H), 1.00 (t, J=7.4Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.5. MS (m/z) 305.21 [M+H]⁺.

Example 35

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pentanamide(35)

Compound (35) was synthesized in a similar fashion to 30B as reported inExample 30, instead replacing methanolic ammonia with1-amino-2-methyl-2-propanol to provide the title compound (35) as itsTFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (dd, J=4.4, 1.4 Hz, 1H),7.87 (dd, J=8.5, 1.4 Hz, 1H), 7.79 (dd, J=8.5, 4.4 Hz, 1H), 4.84-4.78(m, 1H), 3.61 (td, J=5.9, 5.5, 1.5 Hz, 2H), 2.09-1.85 (m, 2H), 1.48(dddd, J=18.0, 13.7, 9.7, 7.3 Hz, 2H), 1.29 (s, 6H), 0.99 (t, J=7.4 Hz,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.5. MS (m/z) 333.25 [M+H]⁺

Example 36

Synthesis of(S)-N-(2-aminoethyl)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanamide(36)

Compound 36 was synthesized in a similar fashion to 30B, insteadreplacing methanolic ammonia with N-Boc-ethylenediamine. Globaldeprotection with TFA furnished the title compound (36) as its bis-TFAsalt. ¹H NMR (400 MHz, Methanol-d4) δ 8.68 (dd, J=4.4, 1.4 Hz, 1H), 7.88(dd, J=8.5, 1.4 Hz, 1H), 7.81 (dd, J=8.5, 4.3 Hz, 1H), 4.92 (dd, J=8.6,5.1 Hz, 1H), 3.56 (ddd, J=13.9, 12.8, 6.7 Hz, 1H), 3.45 (dt, J=14.3, 6.1Hz, 1H), 3.08 (hept, J=6.4 Hz, 2H), 2.13-2.00 (m, 1H), 2.00-1.85 (m,1H), 1.55-1.41 (m, 2H), 0.99 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.6. MS (m/z) 304.05 [M+H]⁺.

Example 37

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(pyridin-2-ylmethyl)pentanamide(37)

Compound 37 was synthesized in a similar fashion to 30B, insteadreplacing methanolic ammonia with 2-picolylamine to provide the titlecompound (37) as the bis TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.69(dd, J=4.4, 1.5 Hz, 1H), 8.65-8.62 (m, 1H), 8.22 (td, J=7.8, 1.7 Hz,1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.81 (dd, J=8.5, 4.4 Hz, 1H), 7.73(d, J=8.0 Hz, 1H), 7.67 (dd, J=7.5, 5.7 Hz, 1H), 4.93 (dd, J=8.8, 5.2Hz, 1H), 4.65 (s, 2H), 2.13-1.94 (m, 3H), 1.57-1.40 (m, 3H), 1.00 (t,J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.8. MS (m/z) 352.04[M+H]⁺.

Example 38

Synthesis of(R)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(38A)

38A was synthesized in a similar fashion to 6A, instead replacing(S)-norvalinol with (R)-2-aminopentanol and2,4-dichloropyrido[3,2-d]pyrimidine with2,4,8-trichloro-6-methylpyrido[3,2-d]pyrimidine. MS (m/z) 446.24 [M+H]⁺.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(38B)

38B was synthesized in a similar fashion to 6B. MS (m/z) 412.22 [M+H]⁺.

Synthesis of(R)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(38C)

Compound 38C was synthesized in a similar fashion to 33, providing thetitle compound (38C) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 4.49 (qd, J=7.9, 6.9,4.1 Hz, 1H), 3.71 (d, J=5.0 Hz, 2H), 2.60 (s, 3H), 1.68 (q, J=7.5 Hz,2H), 1.44-1.33 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.3. MS (m/z) 262.15 [M+H]⁺.

Example 39

Synthesis of(R)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(39A)

39A was synthesized in a similar fashion to 1A, instead replacingbutan-1-amine with (R)-2-aminohexanol and2,4-dichloropyrido[3,2-d]pyrimidine with2,4,8-trichloro-6-methylpyrido[3,2-d]pyrimidine. MS (m/z) 460.21[M+H]⁺.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(39B)

39B was synthesized in a similar fashion to 33. MS (m/z) 426.24 [M+H]⁺.

Synthesis of(R)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(39C)

Compound 39C was synthesized in a similar fashion to 1B to provide thetitle compound (39C) as its TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ7.72 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 4.50 (dt, J=8.4, 5.2 Hz,1H), 3.73 (d, J=5.1 Hz, 2H), 2.63 (s, 3H), 1.80-1.67 (m, 2H), 1.44-1.32(m, 5H), 0.93-0.86 (m, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.3. MS(m/z) 276.17 [M+H]⁺.

Example 40

Synthesis of(S)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(40A)

40A was synthesized in a similar fashion to 1A, replacing butan-1-aminewith (S)-2-aminohexanol and 2,4-dichloropyrido[3,2-d]pyrimidine with2,4,8-trichloro-6-methylpyrido[3,2-d]pyrimidine. MS (m/z) 460.26[M+H]⁺.

Synthesis of(S)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(40b)

40b was synthesized in a similar fashion to 33. MS (m/z) 426.24 [M+H]⁺.

Synthesis of(S)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(40C)

Compound 40C was synthesized in a similar fashion to 1B to provide thetitle compound (40C) as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ7.73 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 4.51 (dq, J=8.5, 6.1,5.4 Hz, 1H), 3.75 (d, J=5.2 Hz, 2H), 2.64 (s, 3H), 1.84-1.65 (m, 3H),1.38 (qd, J=8.0, 6.4, 2.9 Hz, 5H), 0.95-0.87 (m, 4H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.6. MS (m/z) 276.16 [M+H]⁺.

Example 41

N⁴-butyl-7-chloropyrido[3,2-d]pyrimidine-2,4-diamine (41)

Compound 41 was synthesized following the procedure described above forpreparation of 19E, instead reacting intermediate 19B with 1-butan-amineand proceeding with the reported sequence to yield the title compound(41) as the TFA salt after final HPLC purification. ¹H NMR (400 MHz,Methanol-d4) δ 8.56 (d, J=2.1 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 3.66 (t,J=7.3 Hz, 2H), 1.76-1.64 (m, 2H), 1.59 (s, OH), 1.43 (dq, J=14.7, 7.4Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−77.55. MS (m/z) 252.2 [M+H]⁺.

Example 42

(S)-2-((2-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(42B) was prepared according to the following scheme:

(S)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(42A)

Into a vial containing(S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(19D) (50 mg, 0.11 mmol, 1 equiv.) was added NaOMe (65 μL, 1.1 mmol, 10equiv.) and methanol (2 mL). The mixture was heated to 150° C. for 30min. in a microwave reactor. The reaction mixture was partitionedbetween EtOAc and H₂O. The organic layer was separated, dried, andremoved in vacuo. The residue was purified by column chromatography onsilica to provide the title compound. MS (m/z): 428.2 [M+H].⁺

Compound 42B was synthesized via TFA treatment of 42A to yield the titlecompound (42B) as the TFA salt after final HPLC purification. ¹H NMR(400 MHz, Methanol-d4) δ 8.32 (d, J=2.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H),4.57-4.45 (m, 1H), 4.00 (s, 3H), 3.77-3.67 (m, 2H), 1.80-1.63 (m, 2H),1.50-1.39 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.52. MS (m/z) 278.2 [M+H]⁺.

Example 43

Synthesis of(S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(43C)

Methyl 3-amino-5-fluoropicolinate (43A) (830 mg, 4.88 mmol),chloroformamidine hydrochloride (1121.64 mg, 9.76 mmol), dimethylsulfone (4592.09 mg, 48.78 mmol) and a stir bar were charged into asealed pressure tube and heated to 160° C. for 1 hour. At this timereaction was allowed to cool, 50 mL of water was added and the solutionstirred with heating for 30 minutes. Precipitates were filtered off andthe mother liquor was purified by reverse phase HPLC using ACN/H₂O with0.1% TFA as the eluent on a Hydro-RP column with a 2 to 5% ACN gradient.Solvents were removed under reduced pressure and the residue wasazeotroped 2x with methanol, 2x with DCM before sonication in ether.Precipitates were filtered and air dried to afford 210 mg (23.9%) of2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol (43B) as a white solid. ¹HNMR (400 MHz, DMSO-d6) δ 8.43 (d, J=2.5 Hz, 1H), 7.48 (dd, J=10.1, 2.5Hz, 1H), 7.23 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.15, −119.96. MS(m/z) 181.0 [M+H]⁺.

Compound 43C was synthesized via a BOP-C1 promoted coupling of 43B with(S)-norvalinol, which provided the title compound (43C) as its TFA saltafter final HPLC purification. ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (d,J=2.4 Hz, 1H), 7.61 (dd, J=8.8, 2.5 Hz, 1H), 4.56 (dq, J=12.7, 6.4, 6.0Hz, 1H), 3.80-3.69 (m, 2H), 1.78 (ddd, J=18.8, 11.4, 3.7 Hz, 2H),1.53-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.64, −118.17 (d, J=8.8 Hz). MS (m/z) 266.2 [M+H]⁺.

Example 44

(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(44)

Compound 44 was synthesized following the procedure described above forpreparation of 43C, instead reacting intermediate 43B with(R)-norleucinol and proceeding with the above reported sequence to yieldthe title compound (44) as the TFA salt after final HPLC purification.¹H NMR (400 MHz, Methanol-d4) δ 8.57 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8,2.4 Hz, 1H), 4.53 (dq, J=8.7, 5.6 Hz, 1H), 3.72 (d, J=5.4 Hz, 2H), 1.72(m, 2H), 1.52-1.28 (m, 4H), 1.04-0.82 (m, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.60, −118.13 (d, J=8.6 Hz). MS (m/z) 280.2 [M+H]⁺.

Example 45

(S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(45)

Compound 45 was synthesized following the procedure described above forpreparation of 43C, instead reacting intermediate 43B with(S)-norleucinol and proceeding with the above reported sequence to yieldthe title compound (45) as the TFA salt after final HPLC purification.¹H NMR (400 MHz, Methanol-d4) δ 8.57 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8,2.4 Hz, 1H), 4.53 (dq, J=8.7, 5.6 Hz, 1H), 3.72 (d, J=5.4 Hz, 2H), 1.72(m, 2H), 1.52-1.28 (m, 4H), 1.04-0.82 (m, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.60, −118.13 (d, J=8.6 Hz). MS (m/z) 280.2 [M+H]⁺.

Example 46

Synthesis of(R)-2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)hexan-1-ol (46C)

2-amino-6,7-difluoroquinazolin-4-ol (46B) was synthesized following theprocedure described above for preparation of 43B, instead reactingintermediate 46A in place of 43A and proceeding with the above reportedsequence to yield the title compound (46C) as the TFA salt after finalHPLC purification. ¹H NMR (400 MHz, DMSO-d6)¹H NMR (400 MHz, DMSO-d₆) δ7.83 (t, J=9.7 Hz, 1H), 7.31-7.22 (m, 1H), 7.19 (s, 1H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −74.93, −128.78, −144.35. MS (m/z) 198.0 [M+H]⁺.

Compound (46C) was synthesized via a BOP-Cl promoted coupling of 46Bwith (R)-norleucinol, which provided the title compound (46C) as its TFAsalt after final HPLC purification. ¹H NMR (400 MHz, Methanol-d4) δ 8.29(dd, J=11.0, 7.9 Hz, 1H), 7.35 (dd, J=10.6, 6.8 Hz, 1H), 4.67-4.53 (m,1H), 3.80-3.59 (m, 2H), 1.77-1.63 (m, 2H), 1.49-1.30 (m, 4H), 0.91 (td,J=7.0, 6.3, 2.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.71,−127.97 (ddd, J=21.5, 10.6, 7.9 Hz), −142.27 (ddd, J=21.4, 11.0, 6.9Hz). MS (m/z) 297.2 [M+H]⁺.

Example 47

(R)-2-((2-aminoquinazolin-4-yl)amino)hexan-1-ol (47B) was synthesizedvia a BOP-Cl promoted coupling of 47A with (R)-norleucinol, whichprovided the title compound (47B) as its TFA salt after final HPLCpurification. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (ddd, J=8.3, 1.3, 0.6Hz, 1H), 7.78 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.50-7.33 (m, 2H),4.71-4.56 (m, 1H), 3.80-3.61 (m, 2H), 1.81-1.64 (m, 2H), 1.47-1.31 (m,4H), 0.92 (h, J=3.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.69. MS(m/z) 261.1 [M+H]⁺.

Example 48

Synthesis (S)-2-((2-aminoquinazolin-4-yl)amino)hexan-1-ol (48) wasprepared in a similar fashion to 47B, instead using (S)-norleucinol inplace of (R)-norleucinol. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (ddd,J=8.3, 1.3, 0.6 Hz, 1H), 7.78 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.50-7.33(m, 2H), 4.71-4.56 (m, 1H), 3.80-3.61 (m, 2H), 1.81-1.64 (m, 2H),1.47-1.31 (m, 4H), 0.92 (h, J=3.2 Hz, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.69. MS (m/z) 261.1 [M+H]⁺.

Example 49

Synthesis of (S)-tert-butyl(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)propyl)carbamate(49A)

A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) inTHF (2 mL), was treated with (S)-tert-butyl (2-aminopropyl)carbamatehydrochloride butan-1-amine (CAS#959833-70-6, Fluorochem Ltd. UK), (0.03mL, 0.56 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 mmol). Themixture was stirred at rt for 30 minutes, 2,4-dimethoxybenzylamine (0.19ml, 1.25 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) wereadded, and the mixture was heated to 100° C. After 16 h, the reactionwas cooled to rt, diluted with EtOAc, washed with water and brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The resulting residuewas subjected to silica gel chromatography eluting with 0-100% EtOAc inhexanes to provide, after removal of volatiles in vacuo, compound 49A.LCMS (m/z): 469.18[M+H]⁺.

Synthesis of(S)-N⁴-(1-aminopropan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (49)

49A (50 mg, 0.11 mmol) was dissolved in TFA (3 mL). After 30 minutes,the reaction was diluted with water and methanol. After 60 minutes, themixture was concentrated in vacuo. The residue was then dissolved inmethanol and filtered to provide, after removal of volatiles in vacuo,compound 49 as its TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (ddd,J=9.0, 4.2, 1.6 Hz, 1H), 7.85-7.68 (m, 2H), 4.82 (m, 1H), 3.34 (d, 2H),1.39 (d, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.8. LCMS (m/z): 219.03[M+H]⁺; t_(R)=0.29 min. (LC/MS HPLC method B).

Example 50

Synthesis of (R)-2-(2-aminohexyl)isoindoline-1,3-dione hydrochloride(50a)

To phthalimide 51c (180 mg, 0.53 mmol) was added 4N HCl in dioxane (20mL). The reaction was stirred at rt for 6 h and then the volatiles wereremoved in vacuo to provide crude 50a which was carried forward directlyinto the next step without further purification. LCMS (m/z): 246.93[M+H]⁺.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanoate(50b)

A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) inTHF (2 mL) was treated with 50a, (150 mg, 0.53 mmol) andN,N-diisopropylethylamine (0.25 mL, 1.15 mmol). The mixture was stirredat rt for 30 minutes, and 2,4-dimethoxybenzylamine (0.38 mL, 2.5 mmol)and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added and themixture was heated to 125° C. After 24 h, the reaction was cooled to rt,diluted with EtOAc (50 mL), washed with water (25 mL), brine (25 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The resultingresidue was subjected to silica gel chromatography eluting with 0-100%EtOAc in hexanes to give, after removal of volatiles in vacuo, compound50b.

Synthesis of(R)-N⁴-(1-aminohexan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (50)

50b (15 mg, 0.04 mmol) was dissolved in TFA (3 mL). After 60 minutes themixture was concentrated to a residue in vacuo followed byco-evaporation with MeOH, to provide the title compound 50 as itsbis-TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.68 (m, 1H), 7.81-7.83 (m,2H), 4.89 (m, 1H), 3.91 (m, 2H), 3.61 (m, 1H) 1.92-1.79 (m, 2H),1.55-1.48 (m, 4H), 0.98 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz, MeOH-d4) δ−77.9. LCMS (m/z): 261.14 [M+H]⁺; t_(R)=0.30 min.

Example 51

(R)-norleucinol (0.5 g, 4.3 mmol) was treated with Boc₂O (1.2 equiv, 5.2mmol) and excess N,N-diisopropylethylamine in DCM (20 mL). The reactionmixture was stirred for 3h and then filtered through a silica gel plug.Removal of the volatiles provided 51b as a crude residue that was usedwithout further purification. LCMS (m/z): 218.23 [M+H]⁺.

Compound 51b (0.7 g, 3.22 mmol) was reacted with PPh₃ (1.1 g, 3.9 mmol),phthalimide (573 mg, 3.9 mmol), and DIAD (810 mg, 4.0 mmol) in THF (30mL). The mixture was stirred for 3 h, and then partitioned between EtOAc(200 mL) and water (200 mL). The organic layer was separated, washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith 0-100% EtOAc in hexanes to provide 51c. LCMS (m/z): 347.24 [M+H]⁺.

Imide 51c (300 mg, 0.87 mmol) was treated with excess hydrazine hydrate(0.2 mL, 6.25 mmol) in EtOH (30 mL) and refluxed for 16 h. The mixturewas concentrated in vacuo to provide intermediate 51d as a crude residuethat was carried forward directly. Intermediate 51d (0.87 mmol) wasdissolved in DCM (10 mL) and treated with AcCl (0.1 mL, 1.2 mmol),followed by TEA (0.26 mL, 1.8 mmol). The mixture was stirred for 3 h,and then the reaction was diluted with DCM (50 mL). The mixture was thenwashed with water (50 mL), brine (50 mL), dried over Na₂SO₄, filteredand then concentrated under reduced pressure to provide 51e. LCMS (m/z):259.21 [M+H]⁺.

Intermediate 51e (0.3 g) was treated with 4N HCl in dioxanes (20 mL) andstirred for 4 h at rt. The volatiles were removed in vacuo to providethe hydrochloride 51f which was used without further purification. LCMS(m/z): 159.45 [M+H]⁺.

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide(51a)

A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) inTHF (2 mL was treated with 51f, (200 mg, 0.53 mmol) andN,N-diisopropylethylamine (0.25 mL, 1.15 mmol). After the mixture wasstirred for 30 minutes, 2,4-dimethoxybenzylamine (0.38 mL, 2.5 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and themixture was heated to 115° C. After heating for 16 h, the reaction wascooled to rt, diluted with EtOAc (100 mL), washed with water (100 mL),brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The resulting residue was subjected to silica gel flash chromatographyeluting with 0-100% EtOAc in hexanes to provide 51a. LCMS (m/z): 453.33[M+H]⁺.

Synthesis of(R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (51)

51a (60 mg, 0.133 mmol) was dissolved in TFA (3 mL). After 60 minutes,the mixture was concentrated in vacuo. The residue was taken up in MeOH,filtered and concentrated in vacuo, to give the title compound 51 as itsTFA salt. ¹H NMR (400 MHz, MeOH-d₄) 8.65 (dd, J=4.3, 1.5 Hz, 1H),7.86-7.73 (m, 2H), 4.68-4.55 (m, 4H), 3.59 (dd, J=13.9, 4.3 Hz, 4H),3.34-3.23 (m, 3H), 1.88 (s, 3H), 1.78-1.67 (m, 2H), 1.39 (ddd, J=7.7,5.1, 2.4 Hz, 4H), 0.91 (ddt, J=8.3, 4.7, 3.0 Hz, 3H). ¹⁹F NMR (377 MHz,MeOH-d4) δ −77.7. LCMS (m/z): 303.15 [M+H]⁺; t_(R)=0.68 min. (LC/MS HPLCmethod B).

Example 52

N-Boc-protected intermediate 51d (188 mg, 0.87 mmol) was dissolved inDCM (10 mL) and treated with methanesulfonyl chloride (0.78 μL, 114 mg,1 mmol) and TEA (0.26 mL, 1.8 mmol). After 3 h, EtOAc (100 mL) was addedand the resulting mixture washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to provide 52b.LCMS (m/z): 295.24 [M+H]⁺.

Following the synthesis of 51f from 51e, intermediate 52b (0.87 mmol)was converted to the crude hydrochloride salt 52c which was then carriedforward without purification.

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexyl)methanesulfonamide(52A)

A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (50 mg, 0.25 mmol) inTHF (2 mL) was treated with crude 52c, (85 mg, 0.43 mmol) andN,N-diisopropylethylamine (0.25 mL, 1.15 mmol). The mixture was stirredat rt for 30 minutes, 2,4-dimethoxybenzylamine (0.19 mL, 1.25 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and themixture was heated to 115° C. After 16 h, the reaction was cooled to rt,diluted with EtOAc (100 mL), washed with de-ionised water (100 mL),brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was subjected to silica gel chromatography eluting with0-100% EtOAc in hexanes to provide 52A. LCMS (m/z): 489.25 [M+H]⁺.

Synthesis of(R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexyl)methanesulfonamide(52)

52A (30 mg, 0.06 mmol) was dissolved in TFA (3 mL). After 60 minutes,the mixture was concentrated in vacuo. The residue was then diluted withMeOH, filtered, and concentrated in vacuo to afford the title product 52as its TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.65 (dd, J=4.4, 1.4 Hz,1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.58(t, J=6.1 Hz, 1H), 3.52-3.26 (m, 2H), 2.93 (s, 3H), 1.75 (dd, J=9.6, 4.0Hz, 2H), 1.39 (td, J=8.5, 7.6, 3.5 Hz, 4H), 0.91 (m, 3H). ¹⁹F NMR (377MHz, MeOH-d4) δ −77.7. LCMS (m/z): 339.21 [M+H]⁺; t_(R)=0.83 min. (LC/MSHPLC method B).

Example 53

Compound 61C (0.22 g, 0.69 mmol) was mesylated following the procedurefor the formation of 61D but instead replacing acetyl chloride withmethanesulfonyl chloride (0.06 mL, 0.8 mmol) to give a quantitativeyield of the corresponding mesylated intermediate. The resultingsulfonamide was then subjected to Pd/C hydrogenation followed by N-BOCremoval, as described in the preparation of 61E from 61D to give thecrude product 53A as its hydrochloride salt. LCMS (m/z): 209.1 [M+H]⁺.

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)methanesulfonamide(53B)

A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) inTHF (4 mL) was treated with crude 53A (0.69 mmol), andN,N-diisopropylethylamine (0.5 mL, 2.3 mmol). After heating at 75° C.for 4 h, 2,4-dimethoxybenzylamine (0.4 mL, 2.5 mmol) and additionalN,N-diisopropylethylamine (0.26 mL, 1.5 mmol) were added and the mixturewas heated to 115° C. After 16 h, the reaction was cooled to rt, dilutedwith EtOAc (100 mL), washed with de-ionised water (100 mL), brine (100mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was subjected to silica gel chromatography elutingwith 0-100% EtOAc to give 53B. LCMS (m/z): 503.28 [M+H]⁺.

Synthesis of(R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)methanesulfonamide(53)

53B (75 mg, 0.15 mmol) was dissolved in TFA (3 mL). After 60 minutes,the mixture was concentrated in vacuo. The residue was dissolved inMeOH, filtered and volatiles removed in vacuo to afford the titleproduct 53, as its TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.63 (dd,J=4.3, 1.4 Hz, 1H), 7.79 (dd, J=8.4, 1.5 Hz, 1H), 7.73 (dd, J=8.4, 4.3Hz, 1H), 3.78 (m, 2H), 2.93 (s, 3H), 2.25 (m, 1H), 1.82 (dd, J=9.6, 4.0Hz, 2H), 1.56 (s, 3H), 1.37 (td, J=8.4, 7.5, 3.4 Hz, 4H), 0.93 (m, 3H).¹⁹F NMR (377 MHz, MeOH-d4) δ −77.6. LCMS (m/z): 353.18 [M+H]⁺;t_(R)=0.83 min. (LC/MS HPLC method B).

Example 54

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanoate(54A)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (CAS#39551-54-7,supplied by Astatech, Inc.) (500 mg, 2.5 mmol) in THF (10 mL) was addedD-norleucine methyl ester hydrochloride (454 mg, 2.5 mmol) andN,N-diisopropylethylamine (1.3 mL, 7.5 mmol). After stirring at rt for30 minutes, 2,4-dimethoxybenzylamine (1.9 mL, 12.5 mmol) andN,N-diisopropylethylamine (1.3 mL, 7.5 mmol) were added and the mixturewas heated to 100° C. After 16 h, the reaction was cooled to rt, dilutedwith EtOAc (100 mL), washed with water (100 mL), brine (100 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with hexanes-EtOAc toprovide 54A. ¹H NMR (400 MHz, Chloroform-d) δ 8.33 (dd, J=4.2, 1.5 Hz,1H), 7.68 (d, J=7.6 Hz, 1H), 7.43 (dd, J=8.5, 4.2 Hz, 1H), 7.28 (s, 1H),6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.2, 2.4 Hz, 1H), 4.88 (q, J=7.3 Hz,1H), 4.59 (d, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H),2.04-1.95 (m, 1H), 1.88 (dq, J=14.8, 7.6 Hz, 1H), 1.40 (dddd, J=26.8,15.8, 6.9, 2.6 Hz, 5H), 0.91 (t, J=7.1 Hz, 3H). LCMS (m/z): 440.49[M+H]⁺; t_(R)=0.77 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanoicacid (54B)

To a solution of 54A (750.7 mg, 1.71 mL) in THF (3.6 mL) and MeOH (3.6mL) was added iN KOH(a_(q)) (3.6 mL). After 4 h, the reaction was wasneutralized to pH 7 using 1M HCl(a_(q)). Concentration of the mixture invacuo afforded the crude product 54B. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34(d, J=4.1 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=6.5 Hz, 1H), 7.53 (dd,J=8.5, 4.2 Hz, 1H), 7.10 (s, 1H), 6.53 (d, J=2.3 Hz, 1H), 6.42 (dd,J=7.9, 2.0 Hz, 1H), 4.65 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.71 (s,3H), 1.90 (s, 2H), 1.30 (s, 4H), 0.84 (s, 3H). LCMS (m/z): 426.16[M+H]⁺; t_(R)=0.67 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxyethyl)hexanamide(54C)

To a solution of crude 54B (50 mg, 0.12 mmol), N,N-diisopropylethylamine(0.15 mL, 0.86 mmol), and 2-aminoethanol (0.05 mL, 0.59 mmol) in NMP (12mL) was added HATU (96 mg, 0.25 mmol). After 16 h the mixture wassubjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 54C as its TFA salt. LCMS (m/z): 469.23 [M+H]⁺; t_(R)=0.70min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxyethyl)hexanamide(54)

To 54C (10 mg, 0.02 mmol) was added TFA (3 mL). After 4 h, MeOH (2 mL)and water (2 mL) were added to the mixture. After 16 h, the mixture wasconcentrated in vacuo and then co-evaporated with MeOH three times. Theresidue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A,Axia; 10% aq. acetonitrile-60% aq. acetonitrile with 0.1% TFA, over 20min. gradient) to give 54 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ8.68 (dd, J=4.4, 1.5 Hz, 1H), 7.86 (dd, J=8.5, 1.5 Hz, 1H), 7.80 (dd,J=8.5, 4.4 Hz, 1H), 4.81 (dd, J=8.2, 5.7 Hz, 1H), 3.66-3.56 (m, 2H),3.43-3.32 (m, 2H), 2.12-1.90 (m, 2H), 1.49-1.36 (m, 4H), 0.98-0.89 (m,3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.83. LCMS (m/z): 319.23 [M+H]⁺;t_(R)=0.49 min. on LC/MS Method A.

Example 55

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(55A)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.5 mmol)in THF (15 mL) was added (R)-norleucinol (293 mg, 2.5 mmol) andN,N-diisopropylethylamine (1.3 m, 7.5 mmol). After stirring at rt for 30minutes, 2,4-dimethoxybenzylamine (1.9 mL, 12.5 mmol) andN,N-diisopropylethylamine (1.3 mL, 7.5 mmol) were added and the mixturewas heated to 100° C. After 16 h, the reaction was cooled to rt, dilutedwith EtOAc (100 mL), washed with water (100 mL), brine (100 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with hexanes-EtOAc togive 55A. ¹H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.74 (s, 1H),7.46 (s, 1H), 6.49-6.37 (m, 3H), 4.60 (d, J=5.9 Hz, 3H), 3.86 (s, 5H),3.79 (s, 5H), 1.55 (s, 2H), 1.45-1.33 (m, 6H), 0.91 (t, J=7.0 Hz, 4H).LCMS (m/z): 412.20 [M+H]⁺; t_(R)=0.89 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanal(55B)

To a solution of 55A (100 mg, 0.24 mmol) in DCM (5 mL) at 0° C. wasadded Dess-Martin periodinane (248 mg, 0.58 mmol). The reaction waswarmed to rt and stirred for 24 h. The reaction was diluted with DCM (5mL) and then quenched with a mixture of sat. Na₂S₂O_(3(aq)) (5 mL) andsat. NaHCO_(3(aq)) (5 mL). The organic layer was separated and theaqueous layer was extracted with DCM (2×10 mL). The combined organicswere washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with hexanes-EtOAc to give 55B. LCMS (m/z):410.19 [M+H]⁺; t_(R)=0.97 min. on LC/MS Method A.

Synthesis of(R)-N⁴-(1-(1H-imidazol-2-yl)pentyl)-N²-(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine-2,4-diamine(55C)

To a solution of 55B (50 mg, 0.12 mmol) in MeOH (2 mL) was added gyloxaltrimer dihydrate (12 mg, 0.06 mg) and ammonia in MeOH (2M, 0.28 mL, 0.55mmol). After 24 h, additional gyloxal trimer dihydrate (12 mg, 0.06 mg)and ammonia in MeOH (2M, 0.28 mL, 0.55 mmol) were added. After 18 h, themixture was concentrated in vacuo. The residue was diluted with water(10 mL) and extracted with EtOAc (4×10 mL). The combined organics weredried over Na₂SO₄, filtered and concentrated in vacuo to afford thecrude 55C. LCMS (m/z): 448.15 [M+H]⁺; t_(R)=0.62 min. on LC/MS Method A.

Synthesis of(R)-N⁴-(1-(1H-imidazol-2-yl)pentyl)pyrido[3,2-d]pyrimidine-2,4-diamine(55)

To 55C (50 mg, 0.11 mmol) was added TFA (2 mL). After 90 minutes, MeOH(2 mL) and water (2 mL) were added to the mixture. After 16 h, themixture was concentrated in vacuo and co-evaporated with MeOH (×3). Theresidue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A,Axia; 10% aq. acetonitrile-60% aq. acetonitrile with 0.1% TFA, over 20min. gradient) to give 55 as a TFA salt ¹H NMR (400 MHz, MeOH-d₄) δ 8.70(dd, J=4.4, 1.4 Hz, 1H), 7.93 (dd, J=8.5, 1.4 Hz, 1H), 7.83 (dd, J=8.5,4.4 Hz, 1H), 7.52 (s, 2H), 5.92-5.71 (m, 1H), 2.30 (td, J=9.3, 8.7, 4.3Hz, 2H), 1.64-1.34 (m, 4H), 0.95 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz,MeOH-d₄) δ −77.73. LCMS (m/z): 298.05[M+H]⁺; t_(R)=0.46 min. on LC/MSMethod A.

Example 56

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanamide(56A)

To a solution of 54B (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1mL, 0.57 mmol), and ammonia in dioxane (0.5 M, 1.2 mL, 0.59 mmol) in NMP(6 mL) was added HATU (174 mg, 0.46 mmol). After 4 h the mixture wassubjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 56A as a TFA salt. LCMS (m/z): 425.18 [M+H]⁺; t_(R)=0.69 min.on LC/MS Method A.

Synthesis of(R)-N⁴-(1-(4H-1,2,4-triazol-3-yl)pentyl)-N²-(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine-2,4-diamine(56B)

A mixture of 56A (70 mg, 0.17 mmol) and N,N-dimethylformamide dimethylacetal (2 mL, 16 mmol) was heated to 120° C. After 2 h, the mixture wascooled to rt and concentrated in vacuo. The crude residue was dissolvedin AcOH (2 mL) and treated with hydrazine monohydrate (0.02 mL, 0.42mmol). The mixture was heated to 90° C. for 24 h. The mixture wasconcentrated in vacuo to afford the crude 56B which was used withoutfurther purification. LCMS (m/z): 449.23 [M+H]⁺; t_(R)=0.83 min. onLC/MS Method A.

Synthesis of(R)-N⁴-(1-(4H-1,2,4-triazol-3-yl)pentyl)pyrido[3,2-d]pyrimidine-2,4-diamine(56)

To crude 56B was added TFA (3 mL). After 60 minutes, the mixture wasconcentrated in vacuo and the residue was diluted with MeOH (3.5 mL) andwater (3.5 mL). After 90 min., the mixture was concentrated and thensubjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; 10% aq.acetonitrile-60% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 56 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.67 (dd, J=4.4,1.4 Hz, 1H), 8.47 (s, 1H), 7.86 (dd, J=8.5, 1.4 Hz, 1H), 7.79 (dd,J=8.5, 4.4 Hz, 1H), 5.72 (dd, J=8.4, 6.3 Hz, 1H), 2.30-2.09 (m, 2H),1.49-1.34 (m, 4H), 0.96-0.89 (m, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−77.98. LCMS (m/z): 299.15 [M+H]⁺; t_(R)=0.62 min. on LC/MS Method A.

Example 57

2-Chloro-4-methyl-5-nitropyridine (10.0 g, 57.8 mmol) was dissolved inEtOH (100 mL) and Raney nickel (3 g) was added. The reaction mixture wasstirred under H₂ overnight. The mixture was filtered, concentrated undervacuum, and washed with petroleum ether/EtOAc=5:1 (50 mL) to give crude6-chloro-4-methylpyridin-3-amine.

6-Chloro-4-methylpyridin-3-amine (22.0 g, 154.9 mmol) was dissolved inDMF (150 mL) and treated with NIS (41.8 g, 185.9 mmol). The reactionmixture was stirred at rt overnight, then water (200 mL) was added, andthe mixture was extracted with EtOAc (3×200 mL). The combined organicswere concentrated in vacuo and the residue was subjected to silica gelflash chromatography eluting with Et₂zO-EtOAc to give6-chloro-2-iodo-4-methylpyridin-3-amine. ¹H NMR (DMSO-d₆, 400 MHz): δ7.11 (s, 1H), 5.23 (s, 2H), 2.15 (s, 3H) ppm.

To a solution of 6-chloro-2-iodo-4-methylpyridin-3-amine (30.0 g, 111.7mmol) in MeOH (200 mL) was added Pd(dppf)Cl₂ (4.09 g, 5.5 mmol), Et₃N(45.1 g, 447 mmol) and the reaction mixture was stirred at rt overnight.The residue was subjected to silica gel chromatography eluting withEt₂zO-EtOAc to give 6-chloro-2-iodo-4-methylpyridin-3-amine. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.33 (d, J=0.8, 1H), 6.74 (s, 2H), 3.82 (s, 3H),3.18 (d, J=0.4, 3H) ppm.

To a solution of 6-chloro-2-iodo-4-methylpyridin-3-amine (18.8 g, 94mmol) in NH₄OH (180 mL) was added MeOH (10 mL) and the reaction mixturewas stirred at rt overnight. The mixture was filtered and the collectedsolid washed with petroleum ether/EtOAc (5:1, 50 mL) to afford3-amino-6-chloro-4-methylpicolinamide. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.76(s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 6.92 (s, 2H), 2.15 (s, 3H) ppm.

A solution of 3-amino-6-chloro-4-methylpicolinamide (10 g, 54.1 mmol)and CDI (8.02 g; 27.02 mmol) in 1,4-dioxane (200 mL) was stirred at 110°C. for 30 minutes. The mixture was filtered and the collected solidswere washed with EtOAc (30 mL). The organics were concentrated in vacuoto give crude 6-chloro-8-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione.¹H NMR (CDCl₃, 400 MHz) δ 7.70 (d, J=1.2 Hz, 1H), 2.76 (d, J=0.8 Hz, 3H)ppm.

Synthesis of 2,4,6-trichloro-8-methylpyrido[3,2-d]pyrimidine (25A)

A solution of 6-chloro-8-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione(32 g, 151.6 mmol) and N,N-diisopropylethylamine (50 mL) in POCl₃ (320mL) was stirred at 125° C. overnight. The mixture was concentrated invacuo and the residue was subjected to silica gel flash chromatographyeluting with Et₂O-EtOAc to give 25A. ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (d,J=1.2 Hz, 1H), 2.76 (d, J=0.8 Hz, 3H) ppm.

Synthesis of(R)-2-((6-chloro-2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(57A)

To a solution of 25A (50 mg, 0.20 mmol) in THF (15 mL) was addedD-norleucinol (24 mg, 0.20 mmol) and N,N-diisopropylethylamine (1.1 mL,6.0 mmol). After stirring at rt for 30 minutes, 2,4-dimethoxybenzylamine(0.2 mL, 1.1 mmol) and additional N,N-diisopropylethylamine (0.26 mL,1.5 mmol) was added and the mixture was heated to 100° C. After 16 h,the reaction was cooled to rt, diluted with EtOAc (100 mL), washed withwater (100 mL), brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was subjected to silica gelchromatography eluting with hexanes-EtOAc to provide 57A. ¹H NMR (400MHz, Chloroform-d) δ 7.30 (d, J=8.2 Hz, 1H), 7.25 (s, 1H), 6.75 (d,J=6.0 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.2, 2.4 Hz, 1H),5.39 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.85 (s, 4H), 3.81 (d, J=3.1 Hz,1H), 3.79 (s, 4H), 3.68 (q, J=7.7, 7.2 Hz, 1H), 2.51 (s, 3H), 1.72-1.60(m, 3H), 1.46-1.30 (m, 5H), 0.95-0.86 (m, 4H). LCMS (m/z): 460.25[M+H]⁺; t_(R)=1.26 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(57B)

A solution of 57A (35 mg, 0.08 mmol) in EtOAc (4 mL) and EtOH (4 mL) waspurged with Ar, and then Pd/C (Degussa 10 wt %, 25 mg) was added. Themixture was then purged with H₂ and heated to 70° C. After 1 h, thereaction was cooled, purged with Ar, filtered through Celite, and theCelite rinsed with EtOAc. The organics were concentrated in vacuo andthe residue was subjected to silica gel chromatography eluting withEtOAc-MeOH to afford 57B. LCMS (m/z): 426.16 [M+H]⁺; t_(R)=1.18 min. onLC/MS Method A.

Synthesis of(R)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(57)

To 57B (21 mg, 0.05 mmol) was added TFA (3 mL). After 60 minutes, MeOH(5 mL) and water (5 mL) were added to the mixture. After 4 h, themixture was concentrated in vacuo and co-evaporated with MeOH (×3). Theresidue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A,Axia; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20min. gradient) to provide 57 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ8.50 (d, J=4.6 Hz, 1H), 7.63 (dd, J=4.6, 1.0 Hz, 1H), 4.53 (dq, J=8.6,5.2 Hz, 1H), 3.74 (d, J=5.3 Hz, 2H), 2.53 (d, J=0.8 Hz, 4H), 1.83-1.64(m, 3H), 1.45-1.33 (m, 5H), 0.97-0.87 (m, 4H). ¹⁹F NMR (377 MHz,MeOH-d₄) δ −77.78. LCMS (m/z): 276.26 [M+H]⁺; t_(R)=0.88 min. on LC/MSMethod A.

Example 58

Synthesis of(S)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(58)

58 was synthesized in a 3 step procedure similar to that described forExample 57, instead replacing D-norleucinol with L-norleucinol (24 mg,0.204 mmol), affording 58 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ8.48 (d, J=4.6 Hz, 1H), 7.60 (dd, J=4.6, 1.0 Hz, 1H), 4.52 (dq, J=8.7,5.4 Hz, 1H), 3.74 (d, J=5.8 Hz, 2H), 2.52 (d, J=0.8 Hz, 3H), 1.86-1.61(m, 3H), 1.47-1.32 (m, 5H), 0.95-0.86 (m, 4H). ¹⁹F NMR (377 MHz,MeOH-d₄) δ −77.64. LCMS (m/z): 276.17 [M+H]⁺; t_(R)=0.88 min. on LC/MSMethod A.

Example 59

Synthesis of (R)-2-amino-2-methylhexan-1-ol (59A)

To (2R)-2-amino-2-methylhexanoic acid hydrochloride (250 mg, 1.4 mmol,supplied by Astatech) in THF (5 mL) was added borane-tetrahydrofurancomplex solution in THF (1M, 5.5 mL) dropwise over 5 minutes. After 24h, the reaction was quenched with MeOH (1 mL) and concentrated in vacuo.The residue was diluted with DCM, filtered, and concentrated in vacuo toafford crude 59A which was carried forward into the next step directly.LCMS (m/z): 131.92 [M+H]⁺; t_(R)=0.58 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(59B)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (50 mg, 0.25 mmol)in THF (10 mL) was added 59A (50 mg, 0.38 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.75 mmol). After stirring at 80° C.for 18 h, 2,4-dimethoxybenzylamine (0.19 mL, 1.25 mmol) was added andthe mixture was heated to 100° C. After 18 h, the reaction was cooled tort, diluted with EtOAc, washed with water and brine, dried over Na₂SO₄,then filtered and concentrated in vacuo. The residue was subjected tosilica gel chromatography eluting with hexanes-EtOAc to provide 59B.LCMS (m/z): 426.21 [M+H]⁺; t_(R)=0.91 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(59)

To 59B was added TFA (3 mL). After 2 h, the reaction mixture wasconcentrated in vacuo. The residue was subjected to preparative HPLC(Synergi 4u Polar-RP 80A, Axia; 10% aq. acetonitrile-70% aq.acetonitrile with 0.1% TFA, over 20 min. gradient) to provide 59 as aTFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.62 (dd, J=4.2, 1.6 Hz, 1H),7.81 (dd, J=8.5, 1.6 Hz, 1H), 7.77 (dd, J=8.5, 4.2 Hz, 1H), 3.97 (d,J=11.2 Hz, 1H), 3.72 (d, J=11.2 Hz, 1H), 2.18-2.03 (m, 1H), 1.99-1.86(m, 1H), 1.54 (s, 3H), 1.41-1.30 (m, 4H), 0.92 (t, J=6.9 Hz, 2H). ¹⁹FNMR (377 MHz, MeOH-d₄) δ −77.98. LCMS (m/z): 276.13 [M+H]⁺; t_(R)=0.65min. on LC/MS Method A.

Example 60

Synthesis of(S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(60)

Compound 60 was synthesized in a procedure similar to that reported for59, replacing (2R)-2-amino-2-methylhexanoic acid hydrochloride with(2S)-2-amino-2-methylhexanoic acid hydrochloride (250 mg, 1.38 mmol,supplied by Astatech, Inc.). Final purification with preparative HPLC(Synergi 4u Polar-RP 80A, Axia; 10% aq. acetonitrile-70% aq.acetonitrile with 0.1% TFA, over 20 min. gradient) provided 60 as a TFAsalt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.63 (dd, J=4.3, 1.5 Hz, 1H), 7.82(dd, J=8.5, 1.5 Hz, 1H), 7.77 (dd, J=8.5, 4.3 Hz, 1H), 3.98 (d, J=11.2Hz, 1H), 3.73 (d, J=11.2 Hz, 1H), 2.19-2.04 (m, 1H), 2.01-1.88 (m, 1H),1.55 (s, 3H), 1.50-1.29 (m, 4H), 0.93 (t, J=6.9 Hz, 3H). ¹⁹F NMR (377MHz, MeOH-d₄) δ −77.98. LCMS (m/z): 276.10 [M+H]⁺; t_(R)=0.65 min. onLC/MS Method A.

Example 61

Synthesis of (R)-tert-butyl (1-hydroxy-2-methylhexan-2-yl)carbamate(61A)

To a solution of 59A (1 g, 7.6 mmol) in THF (35 mL) was added sat.NaHCO_(3(aq)) (35 mL) followed by di-tert-butyl dicarbonate (3.33 g,15.24 mmol). After 24 h, the organic solvents were removed in vacuo. Theresulting slurry was diluted with water (50 mL), extracted with EtOAc(100 mL), washed with brine (10 mL), dried over Na₂SO₄, and concentratedin vacuo. The residue was subjected to silica gel chromatography usingan ELSD eluting with hexanes-EtOAc to provide 61A. LCMS (m/z): 231.61[M+H]⁺; t_(R)=1.09 min. on LC/MS Method A.

Synthesis of (R)-tert-butyl (2-methyl-1-oxohexan-2-yl)carbamate (61B)

To a solution of 61A (2.1 g, 9.0 mmol) in DCM (100 mL) was addedDess-Martin periodinane (5.7 g, 14 mmol). After 2 h the reaction wasquenched with sat. Na₂S₂O_(3(aq)) (75 mL). The mixture was separated andthe aqueous layer was extracted with DCM (100 mL). The combined organicswere washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄,then filtered and concentrated in vacuo. The residue was subjected tosilica gel chromatography using an ELSD eluting with hexanes-EtOAc toprovide 61B. LCMS (m/z): 173.75 [M+H-(t-Bu)]⁺; t_(R)=1.18 min. on LC/MSMethod A.

Synthesis of (R)-tert-butyl(1-(benzylamino)-2-methylhexan-2-yl)carbamate (61C)

To a solution of 61B (1.9 g, 8.4 mmol) in dry MeOH (50 mL) was addedbenzylamine (1.0 mL, 8.35 mmol). After 18 h, sodium borohydride (500 mg,13 mmol) was added portionwise. At 60 minutes, the mixture wasconcentrated in vacuo. The resulting residue was dissolved in EtOAc (50mL), washed with 1M NaOH_((aq)) (50 mL), 10% Rochelle's salt aq.solution (50 mL, solid supplied by Sigma-Aldrich), and brine (50 mL),dried over Na₂SO₄, then filtered and concentrated in vacuo to afford61C. LCMS (m/z): 321.03 [M+H]⁺; t_(R)=0.94 min. on LC/MS Method A.

Synthesis of (R)-tert-butyl(1-(N-benzylacetamido)-2-methylhexan-2-yl)carbamate (61D)

To a solution of 61C (2.2 g, 6.9 mmol) in THF (50 mL) was addedN,N-diisopropylethylamine (2.4 mL, 14 mmol) followed by acetyl chloride(0.75 mL, 11 mmol). After 60 minutes, the mixture was diluted with EtOAc(150 mL), washed with sat. NaHCO_(3(aq)) (100 mL) and brine (100 mL),dried over Na₂SO₄, then filtered and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting with hexanes-EtOAc toprovide 61D. LCMS (m/z): 362.82 [M+H]⁺; t_(R)=1.32 min. on LC/MS MethodA.

Synthesis of (R)-N-(2-amino-2-methylhexyl)acetamide (61E)

To a solution of 61D (2.0 g, 5.4 mmol) in EtOH (55 mL) and hydrochloricacid solution in dioxane (4M, 2 mL) that was purged with Ar, was addedpalladium hydroxide on carbon (20 wt %, 2.0 g). The mixture was purgedwith H₂ and heated to 60° C. After 24 h, the reaction mixture wasfiltered through Celite, rinsed with EtOAc, and concentrated in vacuo toafford 61E as a HCl salt. LCMS (m/z): 172.92 [M+H]⁺; t_(R)=0.50 min. onLC/MS Method A.

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(61F)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (30 mg, 0.15 mmol)in THF (10 mL) was added 61E (25 mg, 0.15 mmol) andN,N-diisopropylethylamine (0.08 mL, 0.44 mmol). After stirring at 80° C.for 18 h, 2,4-dimethoxybenzylamine (0.1 mL, 0.73 mmol) was added and themixture heated to 100° C. After 18 h, the reaction was cooled to rt,diluted with EtOAc, washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with EtOAc-MeOH to provide 61F. LCMS (m/z):467.24 [M+H]⁺; t_(R)=1.02 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(61)

To 61F (33 mg, 0.07 mmol) was added TFA (3 mL). After 60 minutes, themixture was concentrated in vacuo and co-evaporated with MeOH (×3). Theresidue was suspended in MeOH, filtered, and concentrated in vacuo toprovide 61 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.63 (dd, J=4.4,1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H),3.95 (d, J=14.0 Hz, 1H), 3.57 (d, J=14.0 Hz, 1H), 2.25-2.12 (m, 1H),1.95 (s, 3H), 1.95-1.86 (m, 1H), 1.54 (s, 3H), 1.41-1.32 (m, 4H),0.95-0.90 (m, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.77. LCMS (m/z):317.24 [M+H]⁺; t_(R)=0.71 min. on LC/MS Method A.

Example 62

Synthesis of(R)-N-(2-((6-chloro-2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(62A)

To a solution of 25A (37 mg, 0.15 mmol) in THF (5 mL) was added 61E (25mg, 0.15 mmol) and N,N-diisopropylethylamine (0.4 mL, 0.43 mmol). Afterstirring at 80° C. for 18 h, 2,4-dimethoxybenzylamine (0.1 mL, 0.63mmol) was added and the mixture was heated to 100° C. After 18 h, thereaction was cooled to rt, diluted with EtOAc, washed with water (50 mL)and brine (50 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith EtOAc-MeOH to provide 62A (49 mg, 75%). LCMS (m/z): 515.17 [M+H]⁺;t_(R)=0.86 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(62B)

To a solution of 62A (49 mg, 0.1 mmol) in EtOAc (4 mL) and EtOH (4 mL)that was purged with Ar, was added Pd/C (Degussa 10 wt %, 25 mg). Themixture was then purged with H₂ and heated to 70° C. After 1 h, thereaction was allowed to cool to rt, purged with Ar, filtered throughCelite, rinsed with EtOAc (50 mL), and concentrated in vacuo to provide62B (46 mg, 100%). LCMS (m/z): 481.25 [M+H]⁺; t_(R)=1.10 min. on LC/MSMethod A.

Synthesis of(R)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(62)

To 62B (46 mg, 0.1 mmol) was added TFA (3 mL). After 18 h, the mixturewas concentrated in vacuo and co-evaporated with MeOH (3×10 mL). Theresidue was suspended in 10 mL MeOH, filtered, and concentrated in vacuoto provide 62 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.48 (d, J=4.6Hz, 1H), 7.61 (dd, J=4.7, 1.0 Hz, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.56 (d,J=14.0 Hz, 1H), 2.52 (d, J=0.8 Hz, 3H), 2.18 (ddd, J=13.5, 11.3, 4.5 Hz,1H), 1.95 (s, 3H), 1.89 (ddd, J=13.5, 11.6, 4.8 Hz, 1H), 1.54 (s, 3H),1.42-1.31 (m, 5H), 0.96-0.89 (m, 4H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−77.85. LCMS (m/z): 331.16 [M+H]⁺; t_(R)=0.79 min. on LC/MS Method A.

Example 63

Synthesis of methyl 2-amino-2-methylhexanoate (63A)

To a mixture of (2R)-2-amino-2-methylhexanoic acid hydrochloride (50 mg,0.28 mmol) and (2S)-2-amino-2-methylhexanoic acid hydrochloride (50 mg,0.28 mmol) in MeOH (5.0 mL) was added (trimethylsilyl) diazomethane inhexanes (2 M, 0.41 mL, 0.83 mmol) dropwise. After 6 h, the reaction wasquenched with AcOH (100 μL). The mixture was concentrated in vacuo toprovide 63A that was used without further isolation. LCMS (m/z): 159.91[M+H]⁺; t_(R)=0.57 min. on LC/MS Method A.

Synthesis of methyl2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexanoate(63B)

To a solution of 84E (120 mg, 0.55 mmol) in THF (5 mL) was added 63A (88mg, 0.55 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). Afterstirring at 80° C. for 18 h, the reaction was cooled to rt, diluted withEtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, then filtered and concentrated in vacuo. The crude residue wasthen diluted with THF (10 mL) and 2,4-dimethoxybenzylamine (0.4 mL, 2.6mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) were added. Afterstirring at 100° C. for 18 h, the reaction was cooled to rt, dilutedwith EtOAc (50 mL), washed with water and brine, dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 63B. ¹H NMR(400 MHz, Chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H), 7.36 (s, 1H),7.28-7.24 (m, 2H), 6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.3, 2.4 Hz, 1H),4.54 (dd, J=6.2, 2.7 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H),2.27-2.16 (m, 1H), 2.02 (s, 1H), 1.71 (s, 3H), 1.34-1.23 (m, 5H), 0.88(t, J=6.9 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) 6-121.51 (d, J=422.9Hz). LCMS (m/z): 472.21 [M+H]⁺; t_(R)=0.91 min. on LC/MS Method A.

Synthesis of2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(63C)

To a solution of 63B (104 mg, 0.22 mmol) in THF (5 mL) was added lithiumaluminum hydride in Et₂O (2M, 0.30 mL, 0.60 mmol). After 5 h thereaction was quenched with H₂O (1 mL) and 2M NaOH(a_(q)), and thenfiltered. The mother liquor was then diluted with EtOAc (30 mL), washedwith sat. Rochelle's salt solution (25 mL), H₂O (25 mL), and brine (25mL), dried over Na₂SO₄, then filtered and concentrated in vacuo. Theresidue was subjected to silica gel chromatography eluting withhexanes-EtOAc to provide 63C. ¹H NMR (400 MHz, Chloroform-d) δ 8.12 (d,J=2.5 Hz, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42(dd, J=8.2, 2.4 Hz, 1H), 4.57-4.52 (m, 2H), 3.84 (s, 3H), 3.79 (s, 4H),3.75 (s, 2H), 1.92 (d, J=14.1 Hz, 1H), 1.74 (t, J=12.6 Hz, 1H),1.40-1.37 (m, 3H), 1.32 (td, J=13.4, 12.4, 6.3 Hz, 4H), 0.91 (t, J=7.0Hz, 3H). ¹⁹F NMR (377 MHz, Chloroform-d) 6-121.34. LCMS (m/z): 444.20[M+H]⁺; t_(R)=0.94 min. on LC/MS Method A.

Synthesis of2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(63)

To 63C (22 mg, 0.05 mmol) was added TFA (3 mL). After 30 minutes, thereaction mixture was diluted with MeOH (5 mL). After stirring for 18 h,the mixture was filtered and concentrated in vacuo. Co-evaporation withMeOH (×3) provided 63 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.53(d, J=2.4 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 3.95 (s,1H), 3.70 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13.9, 10.9, 5.3 Hz, 1H),1.96-1.86 (m, 1H), 1.53 (s, 3H), 1.42-1.28 (m, 6H), 0.95-0.87 (m, 3H).¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.47, −118.23 (d, J=8.6 Hz). LCMS (m/z):294.12 [M+H]⁺; t_(R)=0.68 min. on LC/MS Method A.

Example 64

Synthesis of (S)-2-amino-2-methylhexan-1-ol (64A)

To (2S)-2-amino-2-methylhexanoic acid hydrochloride (250 mg, 1.4 mmol,supplied by Astatech) in THF (5 mL) was added borane-tetrahydrofurancomplex solution in THF (1M, 5.5 mL) dropwise over 5 minutes. After 24h, the reaction was quenched with MeOH (1 mL) and concentrated in vacuo.The residue was taken up in DCM (10 mL), filtered, and concentrated invacuo to provide crude 64A. LCMS (m/z): 131.92 [M+H]⁺; t_(R)=0.57 min.on LC/MS Method A.

Synthesis of(S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(64)

To a solution of 43B (140 mg, 78 mmol) and 64A (125 mg, 0.95 mmol) inNMP (7.5 mL), was added DBU (0.35 mL, 2.4 mmol) followed by BOP (419 mg,0.95 mmol). After 16 h, the reaction mixture was subjected to prep HPLC(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-50% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient) to provide, after removal ofvolatiles in vacuo, 64 as a TFA salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.55(d, J=2.4 Hz, 1H), 8.22 (s, 1H), 7.64 (dd, J=8.7, 2.5 Hz, 1H), 3.97 (d,J=11.2 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13.9, 10.8, 5.2Hz, 1H), 1.92 (ddd, J=13.6, 10.9, 5.4 Hz, 1H), 1.54 (s, 4H), 1.40-1.31(m, 5H), 1.00-0.85 (m, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.62, −118.22(d, J=8.7 Hz). LCMS (m/z) 294.09 [M+H]⁺; t_(R)=0.79 min. on LC/MS MethodA.

Example 65

Synthesis of(R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(65A)

To a solution of 19B (112 mg, 0.48 mmol) in THF (5 mL) was added 61E(100 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol).After stirring at 80° C. for 18 h, 2,4-dimethoxybenzylamine (0.75 mL,5.0 mmol) was added and the mixture was heated to 100° C. After 18 h,the reaction was cooled to rt, diluted with EtOAc (50 mL), washed withwater (50 mL) and brine (50 mL), dried over Na₂SO₄, then filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with hexanes-EtOAc to provide 65A LCMS (m/z):509.30[M+H]⁺; t_(R)=0.89 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(65)

To 65A (21 mg, 0.04 mmol) was added TFA (3 mL). After 30 minutes, themixture was concentrated in vacuo and the residue co-evaporated withMeOH (10 mL×3). The resulting residue was suspended in MeOH (10 mL),filtered, and concentrated in vacuo to provide 65 as a TFA salt. ¹H NMR(400 MHz, MeOH-d₄) δ 8.59 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 7.91 (d,J=2.1 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H), 3.52 (d, J=14.0 Hz, 1H),2.22-2.10 (m, 1H), 1.96 (s, 3H), 1.95-1.87 (m, 1H), 1.54 (s, 3H), 1.34(dd, J=7.5, 3.9 Hz, 5H), 0.94-0.89 (m, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−77.91. LCMS (m/z): 351.29 [M+H]⁺; t_(R)=0.69 min. on LC/MS Method A.

Example 66

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(66A)

To 65A (128 mg, 0.26 mmol) in 1,4-dioxane (10 mL) and water (10 mL) wasadded methylboronic acid (61 mg, 1.0 mmol),tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.05 mmol), andpotassium phosphate tribasic (163 mg, 0.77 mmol). The reaction mixturewas heated to 150° C. in a microwave reactor for 30 minutes. Thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(3×25 mL). The combined organics were washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting with EtOAc-MeOH, toprovide 66A. LCMS (m/z): 481.30[M+H]⁺; t_(R)=0.89 min. on LC/MS MethodA.

Synthesis of(R)-N-(2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(66)

To 66A (54 mg, 0.11 mmol) was added TFA (3 mL). After 60 minutes, themixture was concentrated in vacuo and co-evaporated with MeOH (10 mL×3).The resulting residue was suspended in MeOH (10 mL), filtered, andconcentrated in vacuo to provide 66 as a TFA salt. ¹H NMR (400 MHz,MeOH-d₄) δ 8.48 (d, J=1.8 Hz, 1H), 7.64 (s, 1H), 3.94 (d, J=14.0 Hz,1H), 3.57 (d, J=13.9 Hz, 1H), 2.50 (s, 3H), 2.17 (ddd, J=13.4, 11.4, 4.7Hz, 1H), 1.95 (s, 3H), 1.88 (ddd, J=16.1, 8.9, 4.4 Hz, 1H), 1.53 (s,3H), 1.39-1.29 (m, 4H), 0.97-0.86 (m, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−77.86. LCMS (m/z): 331.34 [M+H]⁺; t_(R)=0.93 min. on LC/MS Method A.

Example 67

Synthesis of methyl 3-amino-6-bromo-5-fluoropicolinate (67B)

To a solution of methyl 3-amino-5-fluoropicolinate 67A (270 mg, 2 mmol,1.0 equiv., supplied by Astatech, Inc.) in acetonitrile (2 mL, 0.1Msolution) was added NBS (311 mg, 2.2 mmol, 1.1 equiv.) over 2 minutes atrt. After 18 h, the reaction was quenched with water (50 mL) and themixture was extracted with EtOAc (50 mL), washed with water (50 mL) andbrine (50 mL), then dried over Na₂SO₄, filtered and then concentrated invacuo. The residue was subjected to silica column chromatography elutingwith 0% to 100% EtOAc in hexanes to provide 67B. LCMS (m/z): 250.1[M+H]⁺; t_(R)=0.71 min. on LC/MS Method A.

Synthesis of methyl 3-amino-5-fluoro-6-methylpicolinate (67C)

Methyl 3-amino-6-bromo-5-fluoropicolinate 67B (50 mg, 0.2 mmol, 1equiv.) in a microwave vial was treated with dioxane (2 mL) and water (2mL), along with methylboronic acid (36.05 mg, 0.06 mmol, 3 equiv.),potassium phosphate tribasic (85.23 mg, 0.4 mmol, 2 equiv.) andpalladium(0) tetrakis(triphenylphosphine) (46.4 mg, 0.04 mmol, 0.2equiv.). The mixture was heated to 120° C. for 20 min. and the reactionmixture was partitioned between EtOAc (20 mL) and H₂O (20 mL). Theorganic layers were combined, dried over MgSO₄ then filtered andvolatiles removed in vacuo. The resulting residue was subjected tosilica gel chromatography eluting with 0-100% EtOAc in hexanes toprovide 67C. LCMS (m/z): 184.88 [M+H]⁺; t_(R)=0.54 min. on LC/MS MethodA.

Synthesis of 2-amino-7-fluoro-6-methylpyrido[3,2-d]pyrimidin-4-ol (67D)

A flask containing methyl 3-amino-5-fluoro-6-methylpicolinate 67C (95mg, 0.52 mmol) was treated with chloroformamidine hydrochloride (118 mg,1.03 mmol, supplied by Oakwood Scientific, Inc.). The mixture was heatedto 160° C. overnight. The mixture was allowed to cool to rt, dilutedwith EtOAc (100 mL), filtered, and then the collected solids washed withwater (50 mL) and diethyl ether (50 mL). The solid was allowed to airdry to furnish 67D which was used without further purification. LCMS(m/z): 195.03 [M+H]⁺; t_(R)=0.31 min. on LC/MS Method A.

Synthesis of(S)-2-((2-amino-7-fluoro-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol(67)

To a flask containing2-amino-7-fluoro-6-methylpyrido[3,2-d]pyrimidin-4-ol 67D (5 mg, 0.026mmol) was added DMF (2 mL) along with 1,8-diazabicyclo[5.4.0]undec-7-enesolution 1M in THF (0.01 mL, 0.08 mmol),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(22.78 mg, 0.05 mmol) and (S)-(+)-2-amino-1-pentanol, (10.63 mg, 0.1mmol). The reaction was allowed to stir overnight and then subjected toHPLC (10% to 70% MeCN in water with 0.1% TFA using a Hydro-RP column) toprovide, after removal of volatiles in vacuo, 67 as its TFA salt;t_(R)=0.57 min. on LC/MS Method A. ¹H NMR (400 MHz, MeOH-d₄) δ 7.52 (d,J=9.4 Hz, 1H), 4.54 (s, 1H), 3.73 (d, J=5.3 Hz, 2H), 2.61 (d, J=2.9 Hz,3H), 1.71 (q, J=7.6 Hz, 2H), 1.49-1.37 (m, 1H), 1.29 (s, 5H), 0.97 (t,J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.42; LCMS (m/z): 280.1[M+H]⁺

Example 68

Synthesis of(R)-2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-ol(68A)

Into a microwave vial containing(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol70B (22 mg, 0.049 mmol, 1 equiv.) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (2.35 mg, 0.01mmol), tris(dibenzylideneacetone)dipalladium(0) (0.9 mg, 0.005 mmol, 20mol %) along with dioxane (2.5 mL) and KOH_((aq)) (1 mL, 0.08M). Themixture was heated to 150° C. for 30 min. in a microwave reactor. Thereaction mixture was partitioned between EtOAc (50 ml) and H₂O (50 mL).The organic layer was separated, dried over MgSO₄, filtered andconcentrated in vacuo. The crude material 68A was used without furtherpurification. LCMS (m/z): 428.2 [M+H]⁺; t_(R)=0.78 min. on LC/MS MethodA.

Synthesis of(R)-2-amino-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-ol(68)

A solution of(R)-2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-ol68A (21 mg, 0.05 mmol, 1 equiv.) in DCM (2 mL) was treated with TFA (0.5mL). After 3 h the reaction mixture was concentrated under reducedpressure and the residue subjected to reverse phase HPLC (10% to 70%MeCN in water with 0.1% TFA using a Hydro-RP column) to furnish, afterproduct fraction collection and the removal of volatiles in vacuo, 68 asits TFA salt. LCMS (m/z): 278.3 [M+H]⁺; t_(R)=0.55 min. on LC/MS MethodA. ¹H NMR (400 MHz, MeOH-d₄) δ 8.61-8.34 (m, 1H), 8.19-7.98 (m, 1H),4.39 (ddd, J=18.0, 9.2, 5.3 Hz, 2H), 3.77 (dt, J=8.3, 6.5 Hz, 1H),1.74-1.50 (m, 6H), 1.34-1.09 (m, 10H), 0.79 (tt, J=6.9, 1.3 Hz, 6H),0.59 (d, J=5.6 Hz, 2H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.55

Example 69

Synthesis of 2-amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ol(69B)

Methyl 3-amino-5-(trifluoromethyl)picolinate 69A (300 mg, 0.001 mol, 1equiv., supplied by J&W Pharmlab, LLC) was treated withchloroformamadine hydrochloride (390 mg, 0.003 mmol, 2.5 equiv.) anddimethyl sulfone (1.28 g, 0.014 mol, 10 equiv.). The mixture was heatedto 200° C. overnight. The reaction mixture was allowed to cool to rt,filtered, and washed with water (50 mL) and diethyl ether (50 mL). Theresidue was allowed to air dry to furnish 69B which was used withoutfurther purification. LCMS (m/z): 231 [M+H]⁺; t_(R)=0.48 min. on LC/MSMethod A.

Synthesis of(S)-2-((2-amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(69)

2-amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ol, 69B (100 mg,0.44 mmol, 1 equiv.) was treated with 1,8-diazabicyclo[5.4.0]undec-7-enesolution 1M in THF (0.19 mL, 1.3 mmol, 3 equiv.).(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(249.83 mg, 0.56 mmol, 1.3 equiv.) was added followed by(S)-(+)-2-Amino-1-pentanol (112.06 mg, 1.09 mmol, 2.5 equiv.)), and DMF(5 mL). After stirring 16 h, the reaction mixture was diluted with water(5 mL) and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after productfractions were collected and the volatiles removed in vacuo, the titlecompound 69 as its TFA salt. LCMS (m/z): 316.16 [M+H]⁺; t_(R)=0.59 min.on LC/MS Method A. ¹H NMR (400 MHz, MeOH-d₄) δ 8.94-8.53 (m, 1H), 8.01(dd, J=1.8, 0.9 Hz, 1H), 4.45 (t, J=6.5 Hz, 1H), 3.71-3.54 (m, 2H),3.42-3.24 (m, 2H), 2.72-2.55 (m, 2H), 1.59 (td, J=8.2, 6.6 Hz, 3H),1.37-1.20 (m, 2H), 0.85 (t, J=7.3 Hz, 4H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−64.83, −77.69.

Example 70 & Example 71

Synthesis of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (70A)

A solution of 2,4,7-trichloropyrido[3,2-d]pyrimidine 19B (250 mg, 1.06mmol, 1 equiv.) in dioxane (4 mL) was treated withN,N-diisopropylethylamine (0.22 mL, 1.2 mmol, 1.5 equiv.) and(R)-(−)-2-amino-1-hexanol (312.38 mg, 3.02 mmol, 2.5 equiv.). Thereaction was allowed to stir for 1 h and the product that formed, 70A,was carried forward directly into the following reaction withoutisolation.

Synthesis of(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(70B)

The solution of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol 70A(315 mg, 1.06 mmol, 1 equiv.) prepared as described, was treated withdioxane (4 mL) followed by N,N-diisopropylethylamine (0.38 mL, 2 mmol, 2equiv.) and 2,4-dimethoxybenzylamine (0.47 mL, 3.1 mmol, 3 equiv.). Thereaction was heated at 120° C. overnight. The reaction mixturepartitioned between EtOAc (50 mL) and H₂O (50 mL). The organics layerwas separated, dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith 0% to 100% EtOAc in hexanes to provide the title compound 70B. LCMS(m/z): 446.9 [M+H]⁺; t_(R)=0.78 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(70C)

A microwave vial containing(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol70B (50 mg, 0.11 mmol, 1 equiv.) was treated with potassiumvinyltrifluoroborate (26.59 mg, 0.28 mmol, 2.5 equiv.), potassiumphosphate tribasic (71.4 mg, 0.34 mmol, 3 equiv.), palladium(0)tetrakis(triphenylphosphine) (25.91 mg, 0.02 mmol, 0.2 equiv.), dioxane(2.0 mL), and water (2 mL). The mixture was heated to 150° C. for 60min. in a microwave reactor. The reaction mixture was partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organic layer was separated,dried over Na₂SO₄, filtered and concentrated in vacuo to provide thecrude material 70C which was used without further purification. LCMS(m/z): 438.27 [M+H]⁺; t_(R)=0.82 min. on LC/MS Method A.

Synthesis of(R)-2-((2-amino-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (70)

A solution of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol,70C (49 mg, 0.08 mmol, 1 equiv.) in DCM (2 mL) was treated with TFA (0.5mL). After 3 h the reaction mixture was concentrated under reducedpressure and the residue subjected to reverse phase HPLC (10% to 70%MeCN in water with 0.1% TFA using a Hydro-RP column) to furnish, afterproduct fractions were collected and removal of volatiles in vacuo, 70as its TFA salt. LCMS (m/z): 288.17 [M+H]⁺; t_(R)=0.61 min. on LC/MSMethod A. ¹H NMR (400 MHz, MeOH-d₄) δ 8.61 (d, J=1.8 Hz, 1H), 7.75-7.62(m, 1H), 6.80 (dd, J=17.7, 11.1 Hz, 1H), 6.05 (d, J=17.7 Hz, 1H), 5.54(d, J=11.1 Hz, 1H), 4.47-4.31 (m, 1H), 3.71-3.51 (m, 2H), 1.77-1.47 (m,2H), 1.35-1.16 (m, 5H), 0.93-0.71 (m, 4H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ−77.60.

Synthesis of(R)-2-((2-amino-7-ethylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (71)

(R)-2-((2-amino-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, 70(25 mg, 0.09 mmol, 1 equiv.) was treated with Pd/C (Degussa 10 wt %, 50mg) and EtOH (5 mL) and the mixture stirred under hydrogen. Afterseveral h the solid was filtered off and the filtrate was concentratedunder reduced pressure. The residue was subjected to reverse phase HPLC(10% to 50% MeCN in water with 0.1% TFA using a Gemini C18 column) tofurnish, after product fractions were collected and the removal ofvolatiles in vacuo, 71 as its TFA salt. LCMS (m/z): 290.42 [M+H]⁺;t_(R)=0.70 min. on LC/MS Method A. ¹H NMR (400 MHz, MeOH-d₄) δ 8.60-8.42(m, 1H), 7.63 (td, J=1.6, 0.9 Hz, 1H), 4.61-4.44 (m, 1H), 3.82-3.63 (m,2H), 2.85 (q, J=7.6 Hz, 2H), 1.84-1.64 (m, 3H), 1.46-1.15 (m, 9H),0.97-0.81 (m, 4H). ¹⁹F NMR (377 MHz, MeOH-d₄) δ −77.47.

Example 72

Synthesis of (3R,5R,6S)-tert-butyl3-(but-3-en-1-yl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (72B)

Starting with a stirred solution of (2S,3R)-tert-butyl6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1500 mg, 4 mmol, 1equiv., supplied by Sigma-Aldrich) and 4-iodobutene (3862.41 mg, 0.02mol, 5 equiv., supplied by Sigma-Aldrich) in anhydrous THF (24 mL) andHMPA (2.5 mL), cooled to −78° C., 1M sodium bis(trimethylsilyl) amide inTHF (6.37 mL, 6.37 mmol, 1.5 equiv.) was added dropwise under argon.After 10 min. the reaction mixture was stirred at −40° C. for 4 h. Thereaction was quenched with EtOAc (50 mL) and poured into a mixture ofEtOAc (50 mL) and an aqueous solution of 1M NH₄Cl (50 mL). The organiclayer was separated, washed with water (50 mL) and brine (50 mL), driedwith Na₂SO₄, filtered and volatiles removed in vacuo to give a residue.The residue was subjected to silica gel chromatography eluting with 0%to 100% EtOAc in hexanes to afford the title compound 72B. LCMS (m/z):307.98 [M+H-Boc]+; t_(R)=1.28 min. on LC/MS Method A.

Synthesis of (R)-methyl 2-aminohex-5-enoate (72C)

A 2-neck flask containing lithium (91.98 mg, 13.25 mmol, 15 equiv.) wascooled to −40° C. before liquid ammonia (15 mL) was added to the flaskvia condensation using a cold-finger apparatus. Intermediate 72B (360mg, 0.88 mmol, 1 equiv.) in THF (2 mL) was then added. The reaction wasmaintained at −40° C. for 1 h, and then slowly quenched with NH₄Clsolution (5 mL), after which time it was allowed to warm to rt. Thereaction was then diluted with diethyl ether (50 mL) and water (50 mL)and the diethyl ether layer separated. To the aqueous layer was thenadded 1 N HCl until pH 5 followed by extraction with EtOAc (50 mL). Eachof the organic layers was washed with saturated NH₄Cl (50 mL)separately, and then combined, dried over MgSO₄, filtered andconcentrated in vacuo. DCM (10 mL) was added to the residue followed byMeOH (1 mL), (trimethylsilyl)diazomethane (2.0M solution in hexanes)(0.29 mL, 2.20 mmol, 12 equiv.). After stirring for 1 h the reaction wasconcentrated under reduced pressure. The crude residue was treated withDCM (5 mL) and TFA (5 mL). After stirring for 2 h, the reaction wasconcentrated under reduced pressure to give 72C that was used withoutfurther purification.

Synthesis of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (72D)

A solution of 2,4,-dichloropyrido[3,2-d]pyrimidine (110 mg, 0.55 mmol,1.1 equiv) in dioxane (4 mL) was treated with N,N-diisopropylethylamine(0.14 mL, 0.9 mmol, 2 equiv.) and then the crude (R)-methyl2-aminopent-4-enoate 72C (112 mg, 0.46 mmol, 1 equiv.). The reaction wasallowed to stir for 1 h to provide 72D that was used directly insolution. LCMS (m/z): 307.80 [M+H]⁺; t_(R)=1.09 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-enoate(72E)

The crude solution containing(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol 72D(128 mg, 0.42 mmol, 1 equiv.) was treated with additionalN,N-diisopropylethylamine (0.15 mL, 0.84 mmol, 2 equiv.) and then2,4-dimethoxybenzylamine (0.47 mL, 0.85 mmol, 2 equiv.). The reactionwas heated at 120° C. overnight. The reaction mixture was thenpartitioned between EtOAc (50 mL) and H₂O (50 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered, and then concentrated in vacuo.The residue was subjected to silica gel chromatography eluting with 0%to 100% EtOAc in hexanes to provide the title compound 72E. LCMS (m/z):438.52 [M+H]⁺; t_(R)=0.91 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol(72F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-enoate72E (43 mg, 0.1 mmol, 1 equiv.) was dissolved in THF (5 mL) and 1Mlithium aluminum hydride in diethyl ether (0.29 mL, 0.29 mmol, 3 equiv.)was added. The reaction mixture was stirred at rt for 2 h. The reactionmixture was quenched with water (50 mL) and extracted with EtOAc (50mL). The organic layer was dried over Na₂SO₄, filtered, and thenconcentrated in vacuo. The crude residue 72F (40 mg) was then usedwithout further purification. LCMS (m/z): 410.52 [M+H]⁺; t_(R)=0.85 min.on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol (72)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol72F (40 mg, 0.09 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 72 as its TFA salt.LCMS (m/z): 260.14 [M+H]⁺; t_(R)=0.58 min. on LC/MS Method A. ¹H NMR(400 MHz, MeOH-d₄) δ 8.66 (ddd, J=10.3, 4.2, 1.5 Hz, 1H), 7.94-7.65 (m,2H), 5.86 (ddt, J=16.9, 10.3, 6.7 Hz, 1H), 5.15-4.90 (m, 2H), 4.63-4.43(m, 1H), 2.29-2.06 (m, 2H), 2.00-1.71 (m, 2H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.31, −77.69.

Example 73

Synthesis of (2R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexanoate(73A)

Iron(III) oxalate hexahydrate (172 mg, 0.36 mmol, 2 equiv.) was stirredin water (10 mL) until completely dissolved (typically 1-2 h). The clearyellow solution was cooled to 0° C. and degassed for 10 min. Selectfluor(126 mg, 0.36 mmol, 2 equiv.) and MeCN (5 mL) were added to the reactionmixture. A solution of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-enoate72E (78 mg, 0.18 mmol, 1 equiv.) in MeCN (5 mL) was added to thereaction mixture followed by sodium borohydride (23.6 mg, 0.62 mmol, 3.5equiv.) at 0° C. After 2 min, the reaction mixture was treated with anadditional portion of NaBH₄ (24 mg, 0.62 mmol, 3.5 equiv.). Theresulting mixture was stirred for 30 min. and then quenched by theaddition of 28-30% aqueous NH₄OH (4 mL). The mixture was extracted with10% MeOH in CH₂Cl₂ and the organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was subjected tosilica gel chromatography eluting with 0% to 100% EtOAc in hexanes, toprovide 73A. LCMS (m/z): 458.63 [M+H]⁺; t_(R)=0.91 min. on LC/MS MethodA.

Synthesis of(2R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexan-1-ol(73B)

(2R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexanoate73A (43 mg, 0.1 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.29 mL, 0.29 mmol, 3 equiv.). Thereaction mixture was allowed to stir at rt for 2 h. The reaction mixturewas quenched with water (50 mL) and extracted with EtOAc (50 mL). Theorganics were combined, dried over Na₂SO₄, and concentrated in vacuo.The crude material 73B was used without further purification. LCMS(m/z): 430.19 [M+H]⁺; t_(R)=0.82 min. on LC/MS Method A.

Synthesis of(2R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexan-1-ol(73)

(2R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexan-1-ol73B (40 mg, 0.09 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and the residue subj ected to reverse phase HPLC (10% to 70%MeCN in water with 0.1% TFA using a Hydro-RP column) to furnish, aftercollection of product fractions and removal of volatiles in vacuo, 73 asits TFA salt. LCMS (m/z): 280.12 [M+H]⁺; t_(R)=0.59 min. on LC/MS MethodA. ¹H NMR (400 MHz, Methanol-d₄) δ 8.64 (dd, J=4.3, 1.4 Hz, 1H), 7.84(dd, J=8.5, 1.4 Hz, 1H), 4.63-4.50 (m, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.35(t, J=6.0 Hz, 1H), 3.74 (d, J=5.3 Hz, 2H), 1.89-1.61 (m, 4H), 1.60-1.39(m, 2H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.66, −220.85 (ddd, J=47.6,25.5, 22.1 Hz).

Example 74

Synthesis of (3R,5R,6S)-tert-butyl3-(4-fluorobutyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (74B)

A stirred solution of (2S,3R)-tert-butyl6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1000 mg, 2.8 mmol, 1equiv.) and 1-bromo-4-fluorobutane (2.57 g, 13.5 mmol, 4.5 equiv.,supplied by Sigma-Aldrich) in anhydrous THF (10 mL) and HMPA (1 mL) wascooled to −78° C. and treated dropwise with 1M Lithiumbis(trimethylsilyl) amide in THF (4.2 mL, 4.2 mmol, 1.5 equiv.) underargon. After 10 min. the reaction mixture was stirred at −40° C. for 4h. The reaction was quenched with EtOAc and poured into a mixture ofEtOAc (50 mL) and an aqueous solution of NH₄Cl (50 mL, 1 M). The organiclayer was separated and concentrated in vacuo to provide a crude residuewhich was subjected to silica gel chromatography eluting with 0% to 100%EtOAc in hexanes, to afford the title compound 74B LCMS (m/z): 328.9[M+H-Boc]+; t_(R)=1.38 min. on LC/MS Method A.

Synthesis of (R)-methyl 2-amino-6-fluorohexanoate (74C)

A 2-neck flask containing lithium (170 mg, 24.5 mmol, 15 equiv.) wascooled at −40° C. before liquid ammonia (15 mL) was added via acold-finger. To the deep blue mixture (3R,5R,6S)-tert-butyl3-(4-fluorobutyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate 74B (700mg, 1.6 mmol, 1 equiv.) was added. The reaction mixture was maintainedat this temperature for 1 h and then allowed to warm up to rt. Thereaction was slowly quenched with NH₄Cl solution and diluted withdiethyl ether and the organic layer separated. The aqueous layer wasadjusted to pH 5 with 1N HCl and was then extracted with EtOAc. Theorganic layers were washed with saturated NH₄Cl, dried over MgSO₄,filtered, and concentrated under reduced pressure. The organic residueswere combined and treated with DCM (10 mL) and MeOH (1 mL) along with(trimethylsilyl)diazomethane (2.0M solution in hexanes, 0.50 mL, 3.2mmol, 4 equiv.). After 1 h the reaction mixture was concentrated underreduced pressure. The crude residue material was treated with DCM (5 mL)and TFA (5 mL). The mixture was stirred for 2 h and then concentratedunder reduced pressure to provide crude 74C that was used withoutfurther purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexanoate (74D)

2,4,-dichloropyrido[3,2-d]pyrimidine (163 mg, 0.82 mmol, 1.1 equiv.) wasdissolved in dioxane (6 mL), N,N-diisopropylethylamine (0.53 mL, 2.9mmol, 4 equiv.) and (R)-methyl 2-amino-6-fluorohexanoate 74C (205 mg,0.74 mmol, 1 equiv.). The reaction mixture was stirred for 1h and thenthe mixture of 74D used directly. LCMS (m/z): 326.80 [M+H]⁺; t_(R)=1.04min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexanoate(74E)

A solution of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexanoate74D (243 mg, 0.74 mmol, 1 equiv.) prepared as described, was treatedwith 2,4-dimethoxybenzylamine (0.22 mL, 1.49 mmol, 2 equiv.). Thereaction was heated at 120° C. overnight. The reaction mixture waspartitioned between EtOAc (50 mL) and H₂O (50 mL). The organic layer wasseparated, dried over Na₂SO₄, and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with 0% to 100% EtOAc inhexanes to provide 74E. LCMS (m/z): 445.61[M+H]⁺; t_(R)=0.87 min. onLC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan-1-ol(74F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexanoate74E (236 mg, 0.52 mmol, 1 equiv) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (1.5 mL, 1.54 mmol, 3 equiv.). Thereaction was stirred at rt. After 2 h, the reaction was quenched withwater (50 mL) and extracted with EtOAc (50 mL). The organic layer wasdried over Na₂SO₄, and concentrated in vacuo. The crude material 74F wasused without further purification. LCMS (m/z): 430.52 [M+H]⁺; t_(R)=0.79min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan-1-ol(74)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan-1-ol74F (80 mg, 0.18 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 74 as its TFA salt.LCMS (m/z): 280.15 [M+H]⁺; t_(R)=0.56 min. on LC/MS Method A. ¹H NMR(400 MHz, Methanol-d4) δ 8.64 (dd, J=4.3, 1.4 Hz, 1H), 7.84 (dd, J=8.5,1.4 Hz, 1H), 4.63-4.50 (m, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.35 (t, J=6.0Hz, 1H), 3.74 (d, J=5.3 Hz, 2H), 1.89-1.61 (m, 4H), 1.60-1.39 (m, 2H).¹⁹F NMR (377 MHz, Methanol-d4) δ −77.66, −220.85 (ddd, J=47.6, 25.5,22.1 Hz).

Example 75

Synthesis of (3R,5R,6S)-tert-butyl2-oxo-3-pentyl-5,6-diphenylmorpholine-4-carboxylate (75B)

A stirred solution of (2S,3R)-tert-butyl6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1000 mg, 2.8 mmol, 1equiv., supplied by Sigma-Aldrich) and 1-iodopentane (1.8 mL, 14.2 mmol,5 equiv., supplied by Sigma-Aldrich) in anhydrous THF (15 mL) and HMPA(1.5 mL) cooled to −78° C., was treated dropwise with 1M lithiumbis(trimethylsilyl) amide in THF (4.2 ml, 1.5 equiv.) under argon. After10 min. the reaction mixture was stirred at −40° C. for 4 h. Thereaction mixture was quenched with EtOAc and poured into a mixture ofEtOAc (50 mL) and an aqueous solution of NH₄Cl (50 mL, 1 M). The organiclayer was separated and concentrated in vacuo to provide a crude residuewhich was subjected to silica gel chromatography eluting with 0% to 100%EtOAc in hexanes to afford 75B. LCMS (m/z): 310.08 [M+H]⁺; t_(R)=0.1.33min. on LC/MS Method A.

Synthesis of (R)-methyl 2-aminoheptanoate (75C)

A 2-neck flask containing lithium (110 mg, 15.9 mmol, 15 equiv.) wascooled at −40° C. before liquid ammonia (15 mL) was added via acold-finger. To the deep blue mixture was added (3R,5R,6S)-tert-butyl2-oxo-3-pentyl-5,6-diphenylmorpholine-4-carboxylate 75B (450 mg, 1.06mmol, 1 equiv.). The reaction was maintained at this temperature for 1hand then allowed to warm to rt. The reaction was slowly quenched withNH₄Cl (5 mL) solution and diluted with ether (50 mL) and separated. Tothe aqueous layer was added 1N HCl to pH 5 which was then extracted withEtOAc (50 mL). Each of the organic layers was then washed separatelywith saturated NH₄Cl, then combined, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was treated with DCM(10 mL) and MeOH (1 mL) along with (trimethylsilyl)diazomethane, 2.0Msolution in hexanes (1.1 mL, 2.1 mmol, 4 equiv.). After 1 h the reactionwas concentrated under reduced pressure and the residue dissolved in DCM(5 mL) and TFA (5 mL). The mixture was stirred for 2 h and thenconcentrated under reduced pressure to afford crude 75C which was usedwithout further purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate (75D)

A solution of 2,4,-dichloropyrido[3,2-d]pyrimidine (89 mg, 0.44 mmol,1.2 equiv.) in THF (5 mL) was treated with N,N-diisopropylethylamine(0.26 mL, 1.76 mmol, 4 equiv.) and (R)-methyl 2-aminoheptanoate 75C (71mg, 0.44 mmol, 1 equiv., TFA salt). The reaction was stirred for 1 h andthen the mixture containing 75D was used without purification. LCMS(m/z): 323.8 [M+H]⁺; t_(R)=1.32 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate(75E)

To the solution containing (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate 75D (120 mg,0.37 mmol, 1 equiv.) prepared as described, was added2,4-dimethoxybenzylamine (0.17 mL, 1.1 mmol, 3 equiv.). The reactionmixture was heated at 120° C. overnight. The reaction mixturepartitioned between EtOAc (50 mL) and H₂O (50 mL). The organic layer wasseparated, dried, and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting with 0% to 100% EtOAc in hexanes toprovide the title compound 75E. LCMS (m/z): 454.6 [M+H]⁺; t_(R)=1.02min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol(75F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate75E (169 mg, 0.37 mmol, 1 equiv.) was dissolved in THF (5 mL) andtreated with 1M lithium aluminum hydride in ether (1.1 mL, 1.1 mmol, 3equiv.). The reaction mixture was stirred at rt. After 2 h, the reactionwas quenched with water and extracted with EtOAc. The organics wereseparated, dried, and concentrated in vacuo. The crude product 75F wasused without further purification. LCMS (m/z): 426.4 [M+H]⁺; t_(R)=0.95min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol (75)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol75F (20 mg, 0.05 mmol, 1 equiv.) was dissolved in DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and the residue subjected to reverse phase HPLC (10% to 70%MeCN in water with 0.1% TFA using a Hydro-RP column) to furnish, aftercollection of product fractions and removal of volatiles in vacuo, 75 asits TFA salt. LCMS (m/z): 276.4 [M+H]⁺; t_(R)=0.71 min. on LC/MS MethodA. ¹H NMR (400 MHz, Methanol-d₄) δ 8.65 (dd, J=4.3, 1.6 Hz, 1H),7.92-7.66 (m, 2H), 4.66-4.43 (m, 1H), 3.73 (d, J=5.3 Hz, 2H), 1.81-1.57(m, 2H), 1.51-1.20 (m, 9H), 0.89 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d₄) δ −77.55.

Example 76 and Example 77

Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate(76B)

(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate 76A (6 g,27.37 mmol, supplied by Sigma-Aldrich) was treated with DMF (100 mL) andcooled to 0° C. before methyltriphenoxyphosphonium iodide (16.1 g, 35.58mmol, 1.3 equiv., supplied by Sigma-Aldrich) was slowly added. Thereaction mixture was stirred overnight and solid NaHCO₃ (14 g) and water(100 mL) were added to the reaction. The reaction mixture was stirredfor 15 min. and then the mixture was extracted with hexanes in diethylether, (1:1) (2×250 mL). The combined organic extracts were washed with0.5M NaOH solution (3×75 mL) and saturated NH₄Cl (75 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to afford thecrude product 76B. LCMS (m/z): 331.13 [M+H]⁺; t_(R)=1.16 min. on LC/MSMethod A.

Synthesis of (R)-methyl2-((tert-butoxycarbonyl)amino)-5-methylhex-5-enoate (76C)

Zinc dust (2.4 g, 36.4 mmol, 4 equiv.) was added to iodine (93 mg, 0.37mmol, 0.04 equiv.) in a three-neck round-bottomed flask and heated undervacuum for 10 min. The flask was flushed with nitrogen and evacuatedthree times. (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopranoate76B (3000 mg, 9.11 mmol) was dissolved in dry DMF (5 mL) and added tothe zinc slurry at 0° C. The reaction mixture was stirred at rt for 1 h.Copper (I) bromide-dimethylsulfide complex (187.39 mg, 0.91 mmol, 0.1equiv., supplied by Sigma-Aldrich) was placed in a separate three-neckedflask and gently dried under vacuum until a color change from white togreen was observed. Dry DMF (4 mL) and 3-chloro-2-methylpropene (1.34mL, 13.67 mmol, supplied by Sigma-Aldrich) were added, and the reactionwas cooled to −15° C. Once zinc insertion in the first step wascomplete, stirring was stopped, and the zinc allowed to settle. Thesupernatant was removed via syringe and added dropwise to theelectrophile and Cu catalyst mixture at −15° C. The cold bath wasremoved, and the reaction mixture was stirred at rt for 2 days. EtOAc(100 mL) was added, and the reaction was stirred for 15 min. Thereaction mixture was washed with 1M Na₂S₂O₃ (100 mL), water (2×100 mL),and brine (100 mL), dried over MgSO₄, filtered, and concentrated reducedpressure. The residue was subjected to silica gelchromatography elutingwith 0% to 100% EtOAc in hexane to provide 76C. LCMS (m/z): 157.95[M+H-Boc]+; t_(R)=1.16 min. on LC/MS Method A.

Synthesis of (R)-methyl 2-amino-5-methylhex-5-enoate (76D)

(R)-methyl 2-((tert-butoxycarbonyl)amino)heptanoate 76C (655 mg, 3 mmol)was treated with DCM (5 mL) and TFA (5 mL) and stirred for 2 h. Themixture was then concentrated under reduced pressure to provide 76D thatwas used without further purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate(76E)

2,4,-dichloropyrido[3,2-d]pyrimidine (466 mg, 2 mmol, 1 equiv.) wastreated with THF (10 mL) followed by N,N-diisopropylethylamine (1.66 mL,9 mmol, 4 equiv.), and then (R)-methyl 2-amino-5-methylhex-5-enoate 76D(593 mg, 2 mmol, 1 equiv., TFA salt). The reaction mixture was stirredfor 1 h and then the product 76E was used directly. LCMS (m/z): 321.2[M+H]⁺; t_(R)=1.19 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate(76F)

The solution of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate 76E(748 mg, 2 mmol, 1 equiv.) prepared as described, was treated with2,4-dimethoxybenzylamine (0.69 mL, 5 mmol, 2 equiv.) andN,N-diisopropylethylamine (1.66 mL, 9 mmol, 4 equiv.). The reactionmixture was heated at 120° C. overnight. The reaction mixture waspartitioned between EtOAc (50 mL) and H₂O (50 mL). The organic layer wasseparated, dried over MgSO₄, and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with 0% to 100% EtOAc inhexane to provide the title compound 76F (LCMS (m/z): 452.55 [M+H]⁺;t_(R)=0.97 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexanoate(76G)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate76F (35 mg, 0.08 mmol) was treated with Pd/C (50 mg) and EtOH (5 mL) andthen stirred under hydrogen. After 4 h the solid was removed byfiltration and the filtrate was concentrated under reduced pressure. Theresulting residue of 76G was used without further purification. LCMS(m/z): 454.24 [M+H]⁺; t_(R)=1.06 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexan-1-ol(76H)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexanoate76G (32 mg, 0.37 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.2 mL, 0.2 mmol, 3 equiv.). Thereaction mixture was stirred for 2 h and then quenched with water (50mL) and extracted with EtOAc (50 mL). The organic layer was separated,dried over MgSO₄, and concentrated in vacuo. The crude material 76H wasused without further purification. LCMS (m/z): 426.23 [M+H]⁺; t_(R)=0.96min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexan-1-ol.(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexan-1-ol(76)

Compound 76H (25 mg, 0.05 mmol, 1 equiv.) was treated with DCM (2 mL)and TFA (0.5 mL). After 3 h the reaction mixture was concentrated underreduced pressure and subjected to reverse phase HPLC (10% to 70% MeCN inwater with 0.1% TFA using a Hydro-RP) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 76. LCMS (m/z):276.13 [M+H]⁺; t_(R)=0.70 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-en-1-ol(77A)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate76F (40 mg, 90 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.27 mL, 0.27 mmol, 3 equiv.). Thereaction mixture was stirred for 2 h and then quenched with water (50ml) and extracted with EtOAc (50 mL). The organics were separated,dried, and concentrated in vacuo to provide a residue of 77A that wasused without further purification. LCMS (m/z): 424.20 [M+H]⁺; t_(R)=0.88min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-en-1-ol(77)

77A (40 mg, 0.095 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, the title compound77 as its TFA salt. LCMS (m/z): 274.43 [M+H]⁺; t_(R)=0.65 min. on LC/MSMethod A. ¹H NMR (400 MHz, Methanol-d4) δ 8.59-8.42 (m, 1H), 7.75-7.52(m, 2H), 4.45-4.13 (m, 1H), 3.87-3.69 (m, 1H), 3.65-3.44 (m, 2H), 2.30(dq, J=15.0, 7.1 Hz, 1H), 2.01-1.73 (m, 2H), 1.68-1.41 (m, 4H),1.26-1.05 (m, 6H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.52.

Example 78

Synthesis of (R)-methyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate(78A)

(R)-methyl 2-((tert-butoxycarbonyl)amino)-5-methylhex-5-enoate 76C (775mg, 3.01 mmol) was treated with DCM (20 mL) and MeOH (5 mL) beforecooling to −78° C. Ozone was bubbled through the reaction mixture. After10 min., the mixture was quenched with dimethyl sulfide (0.90 mL, 12mmol, 4 equiv.) and allowed to warm up to rt. EtOAc (100 mL) was added,and the reaction was stirred for 15 min. The mixture was washed with 1MNa₂S₂O₃ (100 mL), water (2×100 mL), and brine (100 mL) and dried overMgSO₄. The organic solution was filtered and concentrated under reducedpressure, and the resulting residue was subjected to silica gelchromatography eluting with 0% to 100% EtOAc in hexane to provide 78A ¹HNMR (400 MHz, Chloroform-d) δ 5.11 (d, J=8.3 Hz, 1H), 4.33-4.20 (m, 1H),3.73 (s, 4H), 2.63-2.42 (m, 3H), 2.14 (s, 4H), 2.12-2.05 (m, 1H),1.94-1.81 (m, 1H), 1.42 (s, 13H).

Synthesis of (R)-methyl2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (78B)

(R)-methyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate 78A (235 mg,0.91 mmol) was dissolved in DCM (10 mL), then treated with DAST 95%(0.36 mL, 2.72 mmol). The reaction was stirred for 16 h. EtOAc (50 mL)and NaHCO₃ solution (5 mL) were added and the reaction was stirred for 5min. The reaction mixture was washed with 1M Na₂S₂O₃ (100 mL), water(2×100 mL), and brine (100 mL) and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue subjected to silica gelchromatography eluting with 0% to 100% EtOAc in hexanes to afford 78B.¹H NMR (400 MHz, Chloroform-d) δ 5.04 (s, 1H), 4.32 (s, 1H), 3.76 (s,5H), 2.16-1.99 (m, 2H), 1.98-1.75 (m, 5H), 1.69-1.52 (m, 7H), 1.44 (s,16H), 1.34-1.20 (m, 2H), 0.92-0.80 (m, 1H). ¹⁹F NMR (377 MHz,Chloroform-d) 6-92.14 (dq, J=50.1, 17.0 Hz).

Synthesis of (R)-methyl 2-amino-5,5-difluorohexanoate (78C)

(R)-methyl 2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate 78B (36mg, 0.13 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA (0.5 mL).After 3 h the reaction mixture was concentrated under reduced pressureand the crude product 78C was used without further purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate(78D)

2,4,-dichloropyrido[3,2-d]pyrimidine (33 mg, 0.16 mmol, 1.25 equiv.) wastreated with THF (10 mL) followed by N,N-diisopropylethylamine (0.18 mL,1.0 mmol, 8 equiv.), and (R)-methyl 2-amino-5,5-difluorohexanoate 78C(36 mg, 0.13 mmol, 1 equiv., TFA salt). The reaction mixture was stirredfor 1 h to generate 78D and then this mixture was used directly. LCMS(m/z): 345.13 [M+H]⁺; t_(R)=1.08 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate(78E)

(R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate 78D(45 mg, 0.13 mmol, 1 equiv.) solution as described, was treated with2,4-dimethoxybenzylamine (0.077 mL, 0.52 mmol, 4 equiv.). The reactionwas heated at 120° C. overnight. The reaction mixture was partitionedbetween EtOAc (100 mL) and H₂O (100 mL). The organics were separated,dried, and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with 0% to 100% EtOAc in hexane to providethe title compound 78E. LCMS (m/z): 476.13 [M+H]⁺; t_(R)=0.99 min. onLC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexan-1-ol(78F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate78E (26 mg, 0.055 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.2 mL, 0.2 mmol, 4 equiv.). Thereaction mixture was stirred at rt for 2 h and then the reaction wasquenched with water (50 mL) and extracted with EtOAc (50 mL). Theorganics were separated, dried, and concentrated in vacuo. The crudematerial 78E was used without further purification. LCMS (m/z): 448.12[M+H]⁺; t_(R)=0.91 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexan-1-ol(78)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexan-1-ol78F (24 mg, 0.055 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 78. LCMS (m/z):298.10 [M+H]⁺; t_(R)=0.60 min. on LC/MS Method A. ¹H NMR (400 MHz,Methanol-d4) δ 8.66 (dd, J=4.3, 1.5 Hz, 5H), 7.86-7.73 (m, 10H), 4.55(dd, J=9.0, 4.7 Hz, 5H), 4.30 (s, 1H), 3.83 (s, 2H), 3.76 (t, J=5.1 Hz,12H), 3.34 (s, 3H), 2.05-1.85 (m, 23H), 1.58 (t, J=18.5 Hz, 17H),1.41-1.26 (m, 17H), 1.14 (s, 1H), 0.96-0.88 (m, 4H), 0.87 (s, 2H). ¹⁹FNMR (377 MHz, Methanol-d4) δ −77.67, −92.96 (p, J=17.4 Hz).

Example 79

Synthesis of (R)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxohexanoate(79A)

Zinc dust (1.58 g, 24.3 mmol, 4 equiv.) was added to iodine (61 mg, 0.24mmol, 0.04 equiv.) in a three-neck round-bottomed flask and heated undervacuum for 10 min. The flask was flushed with nitrogen and evacuatedthree times. After cooling, benzene (10 mL) and DMA (1 mL) were added.1,2-bromoethane (0.05 mL, 0.61 mmol) and chlorotrimethylsilane (33.01mg, 0.3 mmol) were then added consecutively and this process repeatedthree times in the course of 1 hour. (S)-methyl2-((tert-butoxycarbonyl)amino)-3-iodopropanoate 76B (2400 mg, 0.6 mmol,1 equiv.) was dissolved in benzene (10 mL) and DMA (1 mL) and added tothe zinc slurry. After about 1 h, bis(triphenylphosphine) palladium (II)dichloride, (106.62 mg, 0.025 equiv.) andTetrakis(triphenylphosphine)palladium(0) (175.68 mg, 0.025 equiv.) wereadded followed by propionyl chloride (0.8 mL, 0.01 mol, 1.5 equiv.). Thereaction mixture was warmed to 70° C. and stirred for 1 h. EtOAc (100mL) was added, and the reaction mixture was filtered over a pad ofCelite. The filtrate was washed with water (2×100 mL), brine (100 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography eluting with 0% to100% EtOAc in hexane to afford 79A. ¹H NMR (400 MHz, Chloroform-d) δ5.48 (d, J=8.6 Hz, 1H), 4.46 (dt, J=8.7, 4.4 Hz, 1H), 3.69 (s, 3H), 3.10(dd, J=18.0, 4.5 Hz, 1H), 2.89 (dd, J=17.9, 4.4 Hz, 1H), 2.40 (qd,J=7.3, 1.7 Hz, 2H), 1.40 (s, 10H), 1.01 (t, J=7.3 Hz, 3H).

Synthesis of (R)-methyl2-((tert-butoxycarbonyl)amino)-4,4-difluorohexanoate (79B)

(R)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxohexanoate 79A (475 mg,1.8 mmol, 1 equiv.) was treated with DAST (0.97 mL, 7.3 mmol, 4 equiv.).The reaction mixture was stirred for 16 h. EtOAc (50 mL) and NaHCO₃solution (5 mL) were added and the reaction was stirred for 5 min. Thereaction mixture was washed with 1M Na₂S₂O₃ (100 mL), water (2×100 mL),brine (100 mL), dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was subjected to silica gel chromatographyeluting with 0% to 100% EtOAc in hexane to afford 79B. ¹H NMR (400 MHz,Chloroform-d) δ 5.20 (d, J=8.3 Hz, 1H), 4.51 (d, J=7.0 Hz, 1H), 3.82 (s,1H), 3.75 (d, J=0.5 Hz, 5H), 3.35-3.17 (m, 2H), 3.11 (q, J=7.1 Hz, 2H),2.52-2.27 (m, 3H), 1.89 (ddt, J=24.1, 16.8, 7.5 Hz, 3H), 1.44 (d, J=0.6Hz, 15H), 1.23-1.13 (m, 4H), 1.00 (dt, J=10.7, 7.5 Hz, 6H). ¹⁹F NMR (377MHz, Chloroform-d) 6-93.56-−109.28 (m).

Synthesis of (R)-methyl 2-amino-5,5-difluorohexanoate. (R)-methyl2-((tert-butoxycarbonyl)amino)-4,4-difluorohexanoate (79C)

Compound 79B (98 mg, 0.35 mmol, 1 equiv.) was treated with DCM (2 mL)and TFA (0.5 mL). After 3 h the reaction mixture was concentrated underreduced pressure and the crude product 79C as its TFA salt was usedwithout further purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexanoate(79D)

2,4,-dichloropyrido[3,2-d]pyrimidine (80 mg, 0.39 mmol, 1 equiv.) wastreated with THF (10 ml) followed by N,N-diisopropylethylamine (0.28 mL,1.5 mmol, 4 equiv.), and then (R)-methyl 2-amino-5,5-difluorohexanoate79C (110 mg, 0.39 mmol, 1 equiv., TFA salt). The reaction mixture wasstirred for 1 h to form 79D and then this solution was used directly.LCMS (m/z): 345.11 [M+H]⁺; t_(R)=1.09 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexanoate(79E)

(R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate 79Dsolution prepared as described, was treated with2,4-dimethoxybenzylamine (0.077 mL, 0.52 mmol, 4 equiv.). The reactionwas heated at 120° C. overnight. The reaction mixture partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organics were separated,dried over MgSO₄, and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting with 0% to 100% EtOAc in hexane toprovide 79E. LCMS (m/z): 476.32 [M+H]⁺; t_(R)=0.96 min. on LC/MS MethodA.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexan-1-ol(79F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexanoate79E (35 mg, 0.074 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.29 mL, 0.29 mmol, 4 equiv.). Thereaction mixture was stirred for 2 h and then the reaction was quenchedwith water (50 mL) and extracted with EtOAc (50 mE). The organic layerwas separated, dried over MgSO₄, and concentrated in vacuo. The crudematerial 79F was used without further purification. LCMS (m/z): 448.20[M+H]⁺; t_(R)=0.86 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexan-1-ol(79)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexan-1-ol79F (24 mg, 0.055 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 79 as its TFA salt.LCMS (m/z): 298.11 [M+H]⁺; t_(R)=0.63 min. on LC/MS Method A. ¹H NMR(400 MHz, Methanol-d4) δ 8.51 (dd, J=4.3, 1.5 Hz, 1H), 7.77-7.54 (m,2H), 3.60 (d, J=5.7 Hz, 2H), 2.37-2.11 (m, 2H), 1.93-1.69 (m, 2H), 0.87(t, J=7.5 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.80, −98.15,−105.45 (m).

Example 80 and Example 81

Synthesis of (R)-methyl 2-amino-2-methylpent-4-enoate (80B)

(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoicacid 80A (1 g, 2.8 mmol, 1 equiv., provided by Okeanos Inc.) was treatedwith DCM (10 mL) and MeOH (1 mL) along with (trimethylsilyl)diazomethane(2.0M solution in hexanes, 2.3 mL, 5.6 mmol, 2.5 equiv.). After 1 h thereaction mixture was concentrated under reduced pressure to provide aresidue. The residue was treated with THF (10 mL) followed by piperidine(0.56 mL, 0.006 mol, 2 equiv.). The mixture was stirred for 2 h and thenconcentrated under reduced pressure to provide 80B that was used withoutfurther purification.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-enoate(80C)

2,4,-dichloropyrido[3,2-d]pyrimidine (540 mg, 2.71 mmol, 1 equiv.) wastreated with dioxane (15 ml) followed by N,N-diisopropylethylamine (1.9mL, 10.8 mmol, 4 equiv.), and then (R)-methyl2-amino-2-methylpent-4-enoate 80B (486 mg, 2.71 mmol, 1 equiv.). Thereaction mixture was stirred at 80° C. for 15 minutes, then more2,4,-dichloropyrido[3,2-d]pyrimidine (250 mg, 1.25 mmol) was added. Themixture was stirred at 80° C. overnight to form 80C which was then useddirectly. LCMS (m/z): 307.12 [M+H]⁺; t_(R)=1.14 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-enoate(80D)

(R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-enoate 80Csolution prepared as described was treated with 2,4-dimethoxybenzylamine(0.80 mL, 5.0 mmol, 2 equiv.). The reaction was heated at 120° C.overnight. The reaction mixture was partitioned between EtOAc (50 mL)and H₂O (50 mL). The organics were separated, dried over MgSO₄, andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with 0% to 100% EtOAc in hexane to provide 80D.LCMS (m/z): 438.20 [M+H]⁺; t_(R)=1.04 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-en-1-ol(80E)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-enoate80D (634 mg, 1.44 mmol, 1 equiv.) was treated with THF (20 mL) and 1Mlithium aluminum hydride in ether (3.6 mL, 3.62 mmol, 2.5 equiv.). Thereaction mixture was stirred for 2 h and then the reaction was quenchedwith water (100 mL) and extracted with EtOAc (100 mL). The organic layerwas separated, dried over MgSO₄, and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting with 0% to 100% EtOAcin hexane to provide the 80E. LCMS (m/z): 410.17 [M+H]⁺; t_(R)=0.97 min.on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpentan-1-ol(80F)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate80E (35 mg, 0.09 mmol) was treated with Pd/C (60 mg) and EtOH (5 mL) andthen stirred under hydrogen. After 24 h, the solid was filtered off andthe filtrate was concentrated under reduced pressure. The resultingresidue 80F was used without further purification. LCMS (m/z): 454.24[M+H]⁺; t_(R)=1.06 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpentan-1-ol(80)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpentan-1-ol80F (35 mg, 0.09 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 80 as its TFA salt.LCMS (m/z): 262.13 [M+H]⁺; t_(R)=0.64 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-en-1-ol(81)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate80E (40 mg, 0.10 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 4 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 81 as its TFA salt.LCMS (m/z): 260.10 [M+H]⁺; t_(R)=0.63 min. on LC/MS Method A. ¹H NMR(400 MHz, Methanol-d4) δ 8.59 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5,1.4 Hz, 1H), 7.75 (dd, J=8.5, 4.4 Hz, 1H), 5.87 (ddt, J=17.5, 10.1, 7.4Hz, 1H), 5.33-4.94 (m, 2H), 3.94 (d, J=11.2 Hz, 1H), 3.78 (d, J=11.2 Hz,1H), 2.97-2.76 (m, 1H), 2.70 (ddt, J=13.9, 7.3, 1.2 Hz, 1H), 1.55 (s,3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.56.

Example 82

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (82A)

A mixture of 3-amino-5-bromopyridine-2-carboxamide (3.0 g, 13.9 mmol, 1equiv., supplied by Combi-Blocks Inc.), chloroformamidine hydrochloride(3192.9 mg, 27.8 mmol, 2 equiv.), methyl sulfone (13.1 g, 139 mmol, 10equiv.) in sulfolane (1 mL) in a sealed tube, was heated at 165° C.After 24 h, the mixture was diluted with water and then cooled to rt.The reaction was adjusted to pH 12 using NH₄OH and stirred for 20minutes. The precipitates were then filtered, rinsed with water,hexanes, and ether, and dried in a vacuum oven at 1000C overnight toafford 82A that was used without further purification. LCMS (m/z):242.92 [M+H]⁺; t_(R)=0.55 min. on LC/MS Method A.

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl4-methylbenzenesulfonate (82B)

2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol 82A (1000 mg, 4.2 mmol, 1equiv.) was treated with acetonitrile (40 mL) followed by potassiumcarbonate (1433.4 mg, 10.37 mmol, 2.5 equiv.) and p-toluenesulfonylchloride (1186.38 mg, 6.22 mmol, 1.5 equiv.). The reaction mixture washeated to 100° C. and stirred overnight. The mixture was allowed to cooland then diluted with EtOAc, washed with water and saturated NH₄Cl. Theorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure to afford 82B that was used without furtherpurification. LCMS (m/z): 396.98 [M+H]⁺; t_(R)=1.15 min. on LC/MS MethodA.

Synthesis of(R)-2-((2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (82)

2-Amino-7-bromopyrido[3,2-d]pyrimidin-4-yl 4-methylbenzenesulfonate 82B(50 mg, 0.13 mmol, 1 equiv.) was treated with acetonitrile (5 mL),N,N-diisopropylethylamine (0.07 mL, 0.38 mmol, 3 equiv.) and(R)-(−)-2-amino-1-hexanol (44.48 mg, 0.38 mmol, 3 equiv.). After 16 h,the reaction mixture was concentrated under reduced pressure andsubjected to reverse phase HPLC (10% to 70% MeCN in water using aHydro-RP column) to furnish, after collection of product fractions andremoval of volatiles in vacuo, 82 as its TFA salt. LCMS (m/z): 342.1[M+H]⁺; t_(R)=0.90 min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d4)δ 8.69 (d, J=1.9 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 4.52 (dq, J=8.7, 5.5Hz, 1H), 3.86-3.54 (m, 2H), 1.95-1.63 (m, 2H), 1.57-1.29 (m, 5H),1.11-0.76 (m, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.42.

Example 83

Synthesis of (R)-methyl 2-amino-2-methylhex-5-enoate (83B)

(R)-methyl2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylhex-5-enoate 83A(2 g, 5.5 mmol, 1 equiv., provided by Okeanos Inc.) was treated with DCM(20 mL) and MeOH (4 mL) along with (trimethylsilyl)diazomethane (2.0Msolution in hexanes, 4.4 mL, 11.0 mmol, 2.5 equiv.). After 30 minutes,the reaction mixture was concentrated under reduced pressure to providea residue. The residue was treated with THF (33 mL) followed bypiperidine (1.9 mL, 0.02 mol, 3.5 equiv.). The mixture was stirred for 3days and then concentrated under reduced pressure. The residue wassubjected to silica gel chromatography eluting with 0% to 20% MeOH inDCM to provide 83B. LCMS (m/z): 157.91 [M+H]⁺; t_(R)=0.59 min. on LC/MSMethod A.

Synthesis of (R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate(83C)

2,4,-dichloropyrido[3,2-d]pyrimidine (55 mg, 0.28 mmol, 1 equiv.) wastreated with dioxane (15 ml) followed by N,N-diisopropylethylamine (0.25mL, 1.4 mmol, 4 equiv.), and then (R)-methyl2-amino-2-methylhex-5-enoate 83B (47.6 mg, 0.30 mmol, 1 equiv.). Themixture was stirred at 80° C. overnight to form 83C which was useddirectly. LCMS (m/z): 321.14 [M+H]⁺; t_(R)=1.21 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate(83D)

(R)-methyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate 83Csolution prepared as described, was treated with2,4-dimethoxybenzylamine (0.10 mL, 0.69 mmol, 2.5 equiv.). The reactionwas heated at 120° C. overnight. The reaction mixture was partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organics were separated,dried over MgSO₄, and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting with 0% to 100% EtOAc in hexane toprovide 83D. LCMS (m/z): 452.21 [M+H]⁺; t_(R)=1.22 min. on LC/MS MethodA.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol(83E)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate83D (25 mg, 0.06 mmol, 1 equiv.) was treated with THF (20 mL) and 1Mlithium aluminum hydride in ether (0.14 mL, 0.14 mmol, 2.5 equiv.). Thereaction mixture was stirred for 2 h and then the reaction was quenchedwith water (100 mL) and extracted with EtOAc (100 mL). The organic layerwas separated, dried over MgSO4, and concentrated in vacuo to providethe 83E that was used without further purification. LCMS (m/z): 424.14[M+H]⁺; t_(R)=1.12 min. on LC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol(83)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol83E (23 mg, 0.05 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 83 (10 mg, 65%) asits TFA salt. LCMS (m/z): 274.7 [M+H]⁺; t_(R)=0.73 min. on LC/MS MethodA. ¹H NMR (400 MHz, Methanol-d4) δ 9.01 (d, J=4.5 Hz, 1H), 8.33-8.09 (m,2H), 6.23 (ddt, J=16.4, 11.0, 5.8 Hz, 1H), 5.42 (d, J=17.1 Hz, 1H), 4.40(d, J=11.3 Hz, 1H), 4.26-4.03 (m, 2H), 2.57 (ddd, J=29.2, 14.7, 8.4 Hz,3H), 2.42 (dq, J=10.9, 6.9 Hz, 1H), 1.96 (s, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.19 (d, J=144.5 Hz).

Example 84 Synthesis of Intermediate Compound 84E

Synthesis of 3-amino-5-fluoropicolinonitrile (84B)

3-amino-2-bromo-5-fluoropyridine 84A (25 g, 131 mmol, Astatech Chemical,Inc) was treated with ZnCN₂ (16.9 g, 1.1 equiv., 144 mmol), Pd(Ph₃)₄(11.3 g, 0.075 equiv., 9.8 mmol) and DMF (200 mL) and then heated to115° C. After 6 h, the reaction mixture was allowed to cool and thenconcentrated under reduced pressure to a solid. The solid was washedwith EtOAc (2×100 mL). The organic layers were combined and washed withwater (3×100 mL), saturated NH₄Cl solution (100 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to provide 84B that wasused without further purification. LCMS (m/z): 138.87 [M+H]⁺; t_(R)=0.59min. on LC/MS Method A.

Synthesis of 3-amino-5-fluoropicolinamide (84C)

Compound 84B (2.6 g, 19.0 mmol, 1 equiv.) was treated with DMSO (10 mL)and cooled to 0° C. before K₂CO₃ (524 mg, 0.2 equiv., 3.8 mmol) wasadded. H₂O₂ (2.3 mL, 1.2 equiv., 22.8 mmol, 30% water) was then slowlyadded. The cooling bath was removed and the reaction was stirred for 1h. The reaction mixture was diluted with water (100 mL) and extractedwith EtOAc (3×100). The combined organic layers were washed with water(3×500) and saturated NH₄Cl solution (500 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material 84Cwas used without further purification. LCMS (m/z): 155.87 [M+H]⁺;t_(R)=0.62 min. on LC/MS Method A.

The following procedure was adapted from De Jonghe, WO 2006/1359931.

Synthesis of 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol (84D)

Carboxamide 84C (1 g, 1 equiv., 6.4 mmol) was treated with triphosgene(1.9 g, 1.0 equiv., 6.4 mmol) and dioxane (20 mL). The reaction mixturewas heated to 110° C. for 30 min. The reaction mixture was allowed tocool and concentrated under reduced pressure. The crude solid residuewas washed with DCM and diethyl ether and allowed to air dry to provide84D. LCMS (m/z): 181.95 [M+H]⁺; t_(R)=0.62 min. on LC/MS Method A.

Synthesis of 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine (84E)

Dione 84D (13.7 g, 75.6 mmol, 1 equiv.) was treated with phosphoruspentachloride (63.0 g, 302.6 mmol, 4 equiv.) and phosphorus (V)oxychloride (141 mL, 20 equiv.) and heated to 110° C. under a underreflux condenser for 8 h. The reaction mixture was concentrated underreduced pressure and azeotroped with toluene. The resultant solid wastreated with EtOAc (500 mL) and ice-water (500 mL). The organic layerwas separated and washed with saturated NaHCO₃ solution (500 mL), water(500 mL), and saturated NH₄Cl (500 mL). The organic solution was driedover MgSO₄, filtered and concentrated under reduced pressure to furnishthe crude product 84E. LCMS (m/z): 213.9 [M+H+2(OMe)-2Cl]⁺; t_(R)=0.82min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 9.01 (d, J=2.6Hz, 1H), 7.94 (dd, J=7.9, 2.7 Hz, 1H). ¹⁹F NMR (377 MHz, Chloroform-d)6-111.79 (d, J=7.9 Hz).

Synthesis of Compound 84

Synthesis of (R)-methyl2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate(84F)

2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (75 mg, 0.34 mmol, 1equiv.) was treated with dioxane (15 ml) followed byN,N-diisopropylethylamine (0.31 mL, 1.7 mmol, 5 equiv.), and then(R)-methyl 2-amino-2-methylhex-5-enoate 83B (59.5 mg, 0.38 mmol, 1equiv.). The mixture was stirred at 80° C. overnight to form 84F insolution which was then used directly. LCMS (m/z): 339.1 [M+H]⁺;t_(R)=1.23 min. on LC/MS Method A.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate(84G)

(R)-methyl2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate84F solution prepared as described, was treated with2,4-dimethoxybenzylamine (0.10 mL, 0.69 mmol, 2.5 equiv.). The reactionwas heated at 120° C. overnight. The reaction mixture partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organics were separated,dried over MgSO₄, and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting with 0% to 100% EtOAc in hexane toprovide 84G. LCMS (m/z): 470.25 [M+H]⁺; t_(R)=1.12 min. on LC/MS MethodA.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol(84H)

(R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate83G (85 mg, 0.18 mmol, 1 equiv.) was treated with THF (5 mL) and 1Mlithium aluminum hydride in ether (0.54 mL, 0.54 mmol, 3 equiv.). Thereaction mixture was stirred for 2 h and then the reaction was quenchedwith water (100 mL) and extracted with EtOAc (100 mL). The organic layerwas separated, dried over MgSO₄, and concentrated in vacuo to provide84H that was used without further purification. LCMS (m/z): 442.16[M+H]⁺; t_(R)=1.07 min. on LC/MS Method A.

Synthesis of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol(84)

(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol84H (35 mg, 0.08 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 3 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, as its TFA salt.LCMS (m/z): 292.13 [M+H]⁺; t_(R)=0.62 min. on LC/MS Method A. ¹H NMR(400 MHz, Methanol-d4) δ 8.55 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 7.63 (dd,J=8.7, 2.5 Hz, 1H), 5.83 (ddt, J=16.6, 10.2, 6.2 Hz, 1H), 5.02 (dq,J=17.1, 1.5 Hz, 1H), 4.92 (ddt, J=10.2, 2.1, 1.1 Hz, 8H), 4.08-3.88 (m,1H), 3.69 (d, J=11.3 Hz, 1H), 2.34-1.90 (m, 4H), 1.56 (s, 3H). ¹⁹F NMR(377 MHz, Methanol-d4) δ −77.54, −118.17 (dd, J=8.8, 4.3 Hz).

Example 85

Synthesis of ethyl2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate (85B)

2,4,-dichloropyrido[3,2-d]pyrimidine (1068 mg, 5.34 mmol, 1 equiv.) wastreated with dioxane (10 ml) followed by N,N-diisopropylethylamine (5.7mL, 32.0 mmol, 6 equiv.), and then 2-amino-2-ethyl-hexanoic acid ethylester 85A (1000 mg, 5.34 mmol, 1 equiv., supplied by J&W Pharmlab, LLC).The mixture was stirred at 80° C. overnight. The reaction mixturepartitioned between EtOAc (50 mL) and H₂O (50 mL). The organics wereseparated, dried over MgSO₄, and concentrated in vacuo to afford 85Bthat was then used directly. LCMS (m/z): 351.23 [M+H]⁺; t_(R)=1.43 min.on LC/MS Method A.

Synthesis of ethyl2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate(85C)

Ethyl 2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate85B prepared as described, was treated with dioxane (10 mL),N,N-diisopropylethylamine (1.7 mL, 9.5 mmol, 3 equiv.), and2,4-dimethoxybenzylamine (0.94 mL, 6.3 mmol, 2 equiv.). The reaction washeated at 120° C. overnight. The reaction mixture partitioned betweenEtOAc (50 mL) and H₂O (50 mL). The organics were separated, dried overMgSO₄, and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with 0% to 100% EtOAc in hexane to provide85C. LCMS (m/z): 482.27 [M+H]⁺; t_(R)=1.02 min. on LC/MS Method A.

Synthesis of2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol(85D)

Ethyl2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate85C (111 mg, 0.23 mmol, 1 equiv.) was treated with THF (10 mL) and 1Mlithium aluminum hydride in ether (0.92 mL, 0.92 mmol, 4 equiv.). Thereaction mixture was stirred for 2 h and then the reaction was quenchedwith water (100 mL) and extracted with EtOAc (100 mL). The organic layerwas separated, dried over MgSO₄, and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting with 0% to 100% EtOAcin hexane to provide 85D. LCMS (m/z): 440.24 [M+H]⁺; t_(R)=0.94 min. onLC/MS Method A.

Synthesis of2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol (85)

2-((2-((2,4-Diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol85D (16 mg, 0.04 mmol, 1 equiv.) was treated with DCM (2 mL) and TFA(0.5 mL). After 6 h the reaction mixture was concentrated under reducedpressure and subjected to reverse phase HPLC (10% to 70% MeCN in waterwith 0.1% TFA using a Hydro-RP column) to furnish, after collection ofproduct fractions and removal of volatiles in vacuo, 85 as its TFA salt.LCMS (m/z): 290.15 [M+H]⁺; t_(R)=0.73 min. on LC/MS Method A. ¹H NMR(400 MHz, Methanol-d₄) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.93-7.61 (m,2H), 3.98 (s, 3H), 3.91 (s, 2H), 2.10-1.82 (m, 4H), 1.46-1.20 (m, 4H),1.10-0.71 (m, 5H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.69 (d, J=231.2Hz).

Example 86

Synthesis of (R)-2-(Dibenzylamino)hexan-1-ol (86b)

(R)-norleucinol (86a, 2046.4 mg, 17.46 mmol) was treated withacetonitrile (40 mL) and K₂CO₃ (4842.4 mg, 35.04 mmol) followed bybenzyl bromide (6.222 mL, 52.39 mmol) at 0° C. The resulting mixture wasstirred at rt. After 18 h, the precipitate was filtered and the solidswere washed with EtOAc (30 mL). Filtrates were concentrated underreduced pressure and the resultant residue was subjected to silica gelchromatography eluting with 0-70% EtOAc in hexanes to provide 86bLCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₀H₂₈NO: 298.22; found: 298.16;t_(R)=0.82 min on LC/MS Method A.

Synthesis of (R)-2-(dibenzylamino)hexanal (86c)

Oxalyl chloride (0.18 mL, 2.10 mmol) in DCM (3 mL) was cooled in anacetone-dry ice bath and then treated with DMSO (0.3 mL, 4.22 mmol) inDCM (1 mL) dropwise over 2 minutes. After 10 min, a solution of compound86b (503.5 mg, 1.69 mmol) in DCM (2 mL) was added and resulting mixturewas allowed to stir for 30 min. before addition of triethylamine (1.2mL, 8.61 mmol). After 1 h at −70˜−55° C., the reaction mixture wasallowed to warm to rt, diluted with EtOAc (30 mL), and washed with water(30 mL×2). The aqueous fractions were extracted with EtOAc (×1), and thecombined organic fractions were then dried (MgSO₄), concentrated underreduced pressure, and the residue vacuum dried to obtain compound 86c,which was used without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₂₀H₂₆NO: 296.20; found: 296.16; t_(R)=1.12 min on LC/MSMethod A.

Synthesis of (2S,3R)-3-(Dibenzylamino)heptan-2-ol (86d) and(2R,3R)-3-(Dibenzylamino)heptan-2-ol (86e)

Compound 86c (134.87 mg, 0.457 mmol) in diethyl ether (4 mL) was stirredat −15° C. and a 1.6 M solution of methyl lithium in diethyl ether (4.2mL, 6.72 mmol) was added. After 0.5 h, the reaction mixture was quenchedwith saturated aqueous ammonium chloride (10 mL) and water (10 mL), andthe product was extracted with EtOAc (20 mL×2). The organic extractswere washed with water (20 mL×1), combined, dried (MgSO₄), and thenconcentrated under reduced pressure. The crude residue was subjected tosilica gel chromatography eluting with 5-30% EtOAc in hexanes to obtain86d (first eluting compound) and compound 86e second eluting compound.

(2S,3R)-3-(Dibenzylamino)heptan-2-ol (86d)

¹H NMR (400 MHz, Chloroform-d) δ 7.37-7.17 (m, 10H), 4.33 (s, 1H), 3.86(d, J=13.3 Hz, 1.9H), 3.73 (d, J=13.7 Hz, 0.1H), 3.67-3.55 (m, 1H), 3.45(d, J=13.3 Hz, 2H), 2.64 (d, J=5.8 Hz, 0.05H), 2.33 (dt, J=9.3, 5.5 Hz,0.95H), 1.72 (ddd, J=14.8, 12.0, 6.5 Hz, 1H), 1.50-1.20 (m, 6H), 1.18(d, J=6.7 Hz, 0.15H), 1.09 (d, J=6.0 Hz, 2.85H), 0.96 (t, J=7.1 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₃₀NO: 312.23; found: 312.16;t_(R)=0.98 min on LC/MS Method A.

(2R,3R)-3-(Dibenzylamino)heptan-2-ol (86e)

¹H NMR (400 MHz, Chloroform-d) δ 7.44-7.13 (m, 10H), 3.88 (dt, J=8.6,5.8 Hz, 1H), 3.73 (d, J=13.6 Hz, 2H), 3.63 (d, J=13.6 Hz, 2H), 2.65 (td,J=6.5, 4.3 Hz, 1H), 2.31 (s, 1H), 1.73 (td, J=11.0, 9.8, 5.8 Hz, 1H),1.50-1.22 (m, 6H), 1.18 (d, J=6.6 Hz, 3H), 0.92 (t, J=7.0 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₃₀NO: 312.23; found: 312.16;t_(R)=0.93 min on LC/MS Method A.

Synthesis of (2S,3R)-3-aminoheptan-2-ol (86f)

Diastereomer 86d (108.9 mg, 0.349 mmol) and 20% palladium hydroxide oncarbon (25.3 mg) in EtOH (4 mL) was stirred under H₂ atmosphere for 16h. The resulting mixture was filtered and the filtrate was concentratedunder reduced pressure to provide compound 86f contaminated with someEtOH, which was used without further purification. ¹H NMR (400 MHz,Methanol-d4) δ 3.51 (p, J=6.3 Hz, 1H), 2.49 (ddd, J=8.2, 6.0, 4.0 Hz,1H), 1.57-1.20 (m, 6H), 1.15 (d, J=6.4 Hz, 3H), 0.97-0.87 (m, 3H).

Synthesis of(2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(86g)

Compound 86f prepared as described and2,4-dichloropyrido[3,2-d]pyrimidine (73.2 mg, 0.350 mmol, Astatech,Inc.) in THF (3 mL) were treated with N,N-diisopropylethylamine (0.19mL, 1.091 mmol) and the resulting mixture stirred for 1.5 h. AdditionalTHF (3 mL), N,N-diisopropylethylamine (0.19 mL, 1.091 mmol), and2,4-dimethoxybenzylamine (0.27 mL, 1.797 mmol) were added. The reactionmixture was stirred at 100° C. for 15.5 h and then cooled to rt. Thereaction mixture was diluted with DCM (30 mL), washed with water (30mL×2). The aqueous fractions were then extracted with DCM (20 mL×1), andthe combined organic fractions, dried (MgSO₄), and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith 0-20% methanol in DCM to provide crude 86g. The crude 86g wasfurther subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; 10%aq. acetonitrile-80% aq. acetonitrile with 0.1% TFA, over 20 min.gradient). The collected fractions were neutralized with NaHCO₃ beforeconcentration. The residue was dissolved in EtOAc, washed with water,dried (MgSO₄), and concentrated under reduced pressure to providecompound 86g. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₃₂N₅O₃: 426.25;found: 426.14; t_(R)=1.23 min on LC/MS Method A.

Synthesis of(2S,3R)-3-(2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (86)

Compound 86g (76.0 mg, 0.179 mmol) was dissolved in TFA (2 mL) andstirred at rt for 1 h. The reaction mixture was concentrated andco-evaporated with methanol (10 mL×1). The resulting residue wasdissolved in methanol (2 mL) and concentrated ammonium hydroxide (0.2mL) was added to the solution. After 10 min. at rt, the mixture wasconcentrated to dryness, and the residue was dissolved in methanol (3mL) and water (3 mL). The insoluble material was removed by filtration,and the filtrate was subjected to preparative HPLC (Gemini 10u C18 110A,AXIA; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20min. gradient) to provide, after collection of product fractions andremoval of volatiles in vacuo, compound 86 as its TFA salt. ¹H NMR (400MHz, Methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.5Hz, 1H), 7.77 (dd, J=8.5, 4.4 Hz, 1H), 4.37 (td, J=7.2, 3.4 Hz, 1H),3.99 (qd, J=6.4, 3.4 Hz, 1H), 1.76 (q, J=7.4 Hz, 2H), 1.48-1.26 (m, 4H),1.18 (d, J=6.4 Hz, 3H), 0.97-0.82 (m, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₄H22N₅O: 276.18; found: 276.15; t_(R)=0.67 min on LC/MSMethod A.

Example 87

Synthesis of(2S,3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(87)

A solution of 2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol (43B, 20.0 mg,0.068 mmol), compound 86f (27.2 mg, 0.207 mmol), and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 58.9 mg, 0.133 mmol) in DMF (3 mL) was stirred at rt and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.05 mL, 0.333 mmol) was added.After 24 h stirring at rt, the reaction mixture was diluted with water(2 mL) and 1 N HCl (1 mL), and the resulting solution filtered. Thefiltrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA;10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min.gradient). The concentrated fractions containing product wereconcentrated, co-evaporated with methanol (10 mL×3), and then dried invacuo to obtain compound 87 as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.56 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.8, 2.4 Hz, 1H),4.36 (td, J=7.2, 3.6 Hz, 1H), 4.03-3.91 (m, 1H), 1.82-1.69 (m, 2H), 1.37(tddd, J=12.8, 10.3, 7.7, 5.0 Hz, 4H), 1.18 (d, J=6.4 Hz, 3H), 0.94-0.85(m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.82, −117.98 (d, J=8.8 Hz).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₁FN₅O: 294.17; found:294.13; t_(R)=0.71 min on LC/MS Method A.

Example 88

Synthesis of(3R)-3-(dibenzylamino)-1-fluoro-1-(phenylsulfonyl)heptan-2-ol (88a)

A solution of fluoromethyl phenyl sulphone (935.6 mg, 5.371 mmol) in THF(3 mL) was stirred in an acetone-dry ice bath and 2.5 M n-butyllithiumin hexane (2.15 mL) was added. After 30 min, the crude compound 86c(393.9 mg, 1.333 mmol) in THF (2 mL) was added and the resultingsolution stirred with cooling by an acetone-dry ice bath. After 30minutes, the reaction mixture was quenched with saturated NH₄Cl (15 mL),diluted with EtOAc (30 mL), and warmed up to rt before the two fractionswere separated. The aqueous fraction was extracted with EtOAc (20 mL×1),and the organic fractions were then washed with water (30 mL×1), beforebeing combined, dried (MgSO₄), and concentrated under reduced pressure.The residue was subjected to silica gel chromatography eluting with0-40% EtOAc in hexanes to provide compound 88a, as a mixture of 4diastereomers. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₇H₃₃FNO₃S:470.22; found: 470.24; t_(R)=1.40-1.45 min.

Synthesis of (2R,3R)-3-(dibenzylamino)-1-fluoroheptan-2-ol and(2S,3R)-3-(dibenzylamino)-1-fluoroheptan-2-ol (88b and 88c)

A suspension of compound 88a (635.4 mg, 1.333 mmol) and Na₂HPO₄ (1325.9mg, 9.340 mmol) in methanol (10 mL) was stirred in −30˜−40° C. bath assodium-mercury amalgam (1853.9 mmol, 8.060 mmol) was added. The reactionmixture was slowly warmed to ˜5° C. over 2 h and then stirred 1 h at ˜5°C. The mixture was then filtered through a Celite pad and the filtratewas concentrated in vacuo. The residue was dissolved in EtOAc and water(20 mL each), and the two fractions separated. The aqueous fraction wasextracted with EtOAc (20 mL×1). The organic fractions were washed withwater (30 mL×1), then combined, dried (MgSO₄), and concentrated underreduced pressure. The residue was subjected to repeated silica gelchromatography eluting with 5-20% EtOAc in hexanes to provide compound88b, as the first eluting fraction, and compound 88c as the secondeluting fraction.

Compound 88b: ¹H NMR (400 MHz, Chloroform-d) δ 7.63-6.91 (m, 10H),4.53-4.27 (m, 2H), 4.16 (s, 1H), 3.90 (d, J=13.2 Hz, 2H), 3.66 (dt,J=22.5, 5.7 Hz, 1H), 3.49 (d, J=13.3 Hz, 2H), 2.69 (dt, J=9.2, 5.3 Hz,1H), 1.90-1.70 (m, 1H), 1.39 (tdd, J=12.6, 8.2, 5.5 Hz, 5H), 0.97 (t,J=7.0 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) 8-230.59 (td, J=47.8,23.5 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₉FNO: 330.22;found: 330.17; t_(R)=0.96 min on LC/MS Method A.

Compound 88c: ¹H NMR (400 MHz, Chloroform-d) δ 7.54-6.94 (m, 10H), 4.54(ddd, J=47.2, 9.4, 3.4 Hz, 1H), 4.25 (ddd, J=48.2, 9.4, 7.3 Hz, 1H),4.01 (d, J=18.6 Hz, 1H), 3.66 (d, J=2.5 Hz, 4H), 2.68 (q, J=6.1 Hz, 1H),2.35 (s, 1H), 1.88-1.70 (m, 1H), 1.53-1.21 (m, 5H), 1.00-0.80 (m, 3H).¹⁹F NMR (376 MHz, Chloroform-d) 6-228.21 (td, J=47.7, 18.4 Hz).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₉FNO: 330.22; found: 330.13;t_(R)=1.07 min on LC/MS Method A.

Synthesis of (3R)-3-amino-1-fluoroheptan-2-ol (88d)

A mixture of compound 88b (38.25 mg, 0.116 mmol) and 20% palladiumhydroxide on carbon (15.61 mg) in EtOH (2 mL) was stirred under H₂atmosphere. After 20.5 h, the reaction mixture was filtered and thesolids washed with EtOH (10 mL). After the filtrate and washing wasconcentrated, the residue was co-evaporated with toluene (5 mL×2) toobtain compound 88d. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₇H₁₇FNO:150.13; found: 149.97; t_(R)=0.40 min on LC/MS Method A.

Synthesis of(3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(88e)

To a solution of compound 88d (14.9 mg, 0.100 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (11.6 mg, 0.158 mmol) in THF (2 mL)was added N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The mixturewas stirred at rt for 1.5 h and at 50° C. for 30 min. The reactionmixture was then concentrated in vacuo, and the residue subjected tosilica gel chromatography eluting with 20-70% EtOAc in hexanes to obtaincompound 88e. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₁₉ClFN₄O:313.12; found: 313.14; t_(R)=1.06 min on LC/MS Method A.

Synthesis of(3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(88f)

To solution of compound 88e (22.0 mg, 0.070 mmol) in dioxane (2 mL),N,N-diisopropylethylamine (0.06 mL, 0.344 mmol), and2,4-dimethoxybenzylamine (0.04 mL, 0.266 mmol) were added. The resultingsolution was refluxed at 110° C. for 19 h. After the reaction mixturewas concentrated, the residue was subjected to silica gel chromatographyeluting with hexanes-EtOAc to provide crude product 88f. The crudeproduct was then subjected to preparative HPLC (Gemini 10u C18 110A,AXIA; 10% aq. acetonitrile-80% aq. acetonitrile with 0.1% TFA, over 20min. gradient). The combined product fractions were neutralized by theaddition of saturated aqueous NaHCO₃ (1 mL), concentrated to removeacetonitrile, and then extracted with EtOAc (20 mL×2). The organicextracts were washed with water (×1), combined, dried (MgSO₄), andconcentrated under reduced pressure to obtain compound 88f LCMS-ESI⁺(m/z): [M+H-C₂H4]+calculated for C₂₃H₃₁FN₅O₃: 444.24; found: 444.18;t_(R)=0.95 min on LC/MS Method A.

Synthesis of(3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(88)

Compound 88f (8.7 mg, 30.44 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was concentrated in vacuoand co-evaporated with methanol (10 mL). The residue was dissolved inmethanol (1 mL) and concentrated ammonium hydroxide (0.1 mL) was added.The resulting mixture was stirred at rt for 10 min, concentrated underreduced pressure. The residue was triturated in 1 N HCl (0.5 mL) andmethanol (2 mL), filtered, and diluted with water (3 mL) beforesubjecting to preparative HPLC (Gemini 10u C18 110A, AXIA; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient).The product fractions were combined, concentrated in vacuo,co-evaporated with methanol (10 mL×3) and dried in vacuo to obtaincompound 88 as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dd,J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.77 (dd, J=8.5, 4.4Hz, 1H), 4.59 (ddd, J=8.0, 6.5, 3.0 Hz, 1H), 4.51-4.38 (m, 1H),4.38-4.26 (m, 1H), 4.04 (dddd, J=16.2, 6.1, 4.9, 3.1 Hz, 1H), 1.89-1.73(m, 2H), 1.39 (dtd, J=10.4, 6.9, 6.3, 3.4 Hz, 4H), 0.96-0.84 (m, 3H).¹⁹F NMR (376 MHz, Methanol-d4) δ −77.56, −231.26 (td, J=47.3, 16.2 Hz).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₁FN₅O: 294.17; found:294.15; t_(R)=0.69 min on LC/MS Method A.

Example 89

Synthesis of (2S,3R)-3-(dibenzylamino)-1,1,1-trifluoroheptan-2-ol (89a)and (2R,3R)-3-(dibenzylamino)-1,1,1-trifluoroheptan-2-ol (89b)

A solution of compound 86c (492.7 mg, 1.668 mmol) and tetrabutylammoniumfluoride (TBAF, 21.8 mg, 0.083 mmol) in THF (4 mL) was stirred at 0° C.and trimethyl(trifluoromethyl)silane (0.76 mL, 5.17 mmol) was added.After the resulting mixture was stirred at 0° C. for 30 min, additionalTBAF (87.2 mg, 0.334 mmol) was added and the reaction mixture wasstirred for 1h at rt. The reaction mixture was quenched with saturatedaqueous NH₄Cl (10 mL). The resulting solution was diluted with EtOAc (20mL) and two layers were separated. The aqueous fraction was extractedwith EtOAc (20 mL×3) and the organic fractions were washed with brine(20 mL×1), combined, dried (MgSO₄), and concentrated in vacuo. Theresidue was then subjected to silica gel chromatography eluting with0-20% EtOAc in hexanes to obtain compound 89a, as the first elutingproduct and compound 89b as the second eluting product.

Compound 89a: ¹H NMR (400 MHz, Chloroform-d) δ 7.36-7.26 (m, 10H), 5.30(s, 1H), 3.90 (d, J=13.1 Hz, 2H), 3.74-3.64 (m, 1H), 3.60 (d, J=13.1 Hz,2H), 2.97 (d, J=9.3 Hz, 1H), 1.94-1.80 (m, 1H), 1.60-1.44 (m, 3H), 1.38(h, J=7.4 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −76.57 (d, J=6.3 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₂₁H₂₇F₃NO: 366.20; found: 366.15; TR=1.46 min.

Compound 89b: ¹H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J=4.8 Hz, 10H),4.22 (s, 1H), 3.82 (d, J=13.6 Hz, 2H), 3.50 (d, J=13.6 Hz, 2H), 3.00 (d,J=9.4 Hz, 1H), 2.66 (s, 1H), 1.79 (q, J=9.1 Hz, 1H), 1.49 (s, 2H),1.35-1.11 (m, 4H), 0.87 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz,Chloroform-d) 8-76.53 (d, J=8.3 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₂₁H₂₇F₃NO: 366.20; found: 366.15; t_(R)=1.49 min on LC/MS Method A.

Synthesis of (2R,3R)-3-amino-1,1,1-trifluoroheptan-2-ol (89c)

To a stirred solution of compound 89a (121.35 mg, 0.332 mmol) in EtOH (4mL) was added 20% palladium hydroxide on carbon (52 mg, 0.074 mmol). Theresulting mixture was stirred under H₂ atmosphere for 20 h. The reactionmixture was then filtered and washed with ethanol (10 mL). The filtratewas then concentrated in vacuo to obtain compound 89c. LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₇H₁₅F₃NO: 186.11; found: 185.96; t_(R)=0.55 minon LC/MS Method A.

Synthesis of(2R,3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1-trifluoroheptan-2-ol(89d)

To a solution of compound 89c (53.4 mg, 0.288 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (57.68 mg, 0.288 mmol) in THF (3 mL)was added N,N-diisopropylethylamine (0.151 mL, 0.865 mmol) and themixture heated to 80° C. After 2 h, the reaction mixture was allowed tocool to rt and then concentrated in vacuo and the residue subjected tosilica gel chromatography eluting with 0-100% EtOAc in hexanes to affordcompound 89d.

Synthesis of(2R,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1-trifluoroheptan-2-ol(89e)

To a solution of compound 89d (106.7 mg, 0.346 mmol) in dioxane (3 mL)was added N,N-diisopropylethylamine (0.160 mL, 0.918 mmol) and2,4-dimethoxybenzylamine (0.230 mL, 1.530 mmol). The resulting solutionwas refluxed at 110° C. and stirred for 20 h. The reaction mixture wasthen cooled to rt and diluted with EtOAc (20 mL), washed with water (20mL×3) and brine (20 mL×1), dried (MgSO₄), filtered and then concentratedin vacuo. The residue was subjected to silica gel chromatography elutingwith 0-100% EtOAc in hexanes to afford compound 89e. LCMS-ESI⁺ (m/z):[M+H-C₂H₄]⁺ calculated for C₂₃H₂₉F₃N₅O₃: 480.22; found: 480.17;t_(R)=1.03 min on LC/MS Method A.

Synthesis of(2R,3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1-trifluoroheptan-2-ol(89)

Compound 89e (12 mg, 25.0 umol) was dissolved in TFA (1 mL) and stirredat rt for 1 h. The reaction mixture was concentrated in vacuo andco-evaporated with methanol (10 mL). The resulting residue was dissolvedin aqueous methanol (1 mL), filtered through a Celite-membrane filter toremove insoluble material, and the filtrate subjected to preparativeHPLC (Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq.acetonitrile with 0.1% TFA, over 20 min. gradient). The collectedproduct fractions were concentrated in vacuo, and the residue wasco-evaporated with methanol (10 mL×3), and dried in vacuum overnight toobtain compound 89 as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.65(dd, J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H), 7.79 (dd, J=8.5,4.4 Hz, 1H), 4.82 (ddd, J=8.3, 6.5, 2.1 Hz, 1H), 4.22 (qd, J=7.3, 1.9Hz, 1H), 1.92-1.74 (m, 2H), 1.50-1.31 (m, 4H), 0.96-0.87 (m, 3H). ¹⁹FNMR (376 MHz, Methanol-d₄) δ −77.56, −79.32 (d, J=7.3 Hz). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₄H₁₉F₃N₅O: 330.15; found: 330.15;t_(R)=0.77 min on LC/MS Method A.

Example 90

Synthesis of(2R,3R)-3-(dibenzylamino)-1,1-difluoro-1-(phenylsulfonyl)heptan-2-ol and(2S,3R)-3-(dibenzylamino)-1,1-difluoro-1-(phenylsulfonyl)heptan-2-ol(90a and 90b)

A solution of compound 86c (235.6 mg, 0.798 mmol) and difluoromethylphenyl sulfone (153.3 mg, 0.80 mmol) in THF (5 mL) was stirred at −78°C. and then 1.0 M LHMDS in THF (1.60 mL, 1.60 mmol) was added slowly.The reaction mixture was stirred for 2 h at −78° C., and warmed to rt.before quenching with saturated aqueous NH₄Cl solution (15 mL). Theresulting solution was diluted with EtOAc (25 mL) and the two layersseparated. The separated aqueous fraction was back extracted with EtOAc(15 mL×2). The separate organic fractions were washed with water (25mL×2), brine (25 mL), then combined, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with 0-30% EtOAc in hexanes to afford of compound90a as the first eluting isomer, and compound 90b as the second elutingisomer.

Compound 90a. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₇H₃₂F₂NO₃S:488.21; found: 488.20; t_(R)=1.50 min on LC/MS Method A.

Compound 90b. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₇H₃₂F₂NO₃S:488.21; found: 488.23; t_(R)=1.52 min on LC/MS Method A.

Synthesis of (3R)-3-(dibenzylamino)-1,1-difluoroheptan-2-ol (90c)

To a solution of compound 90a (132.9 mg, 0.273 mmol) in methanol (2 mL)at −40° C. was added Na₂HPO₄ (236.3 mg, 1.664 mmol) and 5% sodiummercury-amalgam beads (646.1 mg, 1.41 mmol). The resulting mixture wasstirred for 2 h in a cold bath, and then filtered through a Celite pad.The filtrate was concentrated in vacuo and the residue was treated withEtOAc (20 mL) and water (20 mL). The two layers were separated and theaqueous fraction was extracted with EtOAc (20 mL×2). The organicfractions were washed with water (20 mL×1), then combined, dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography eluting with 0-30% EtOAc inhexanes to provide compound 90c. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₁H₂₈F₂NO: 348.21; found: 348.16; t_(R)=1.26 min on LC/MS Method A.

Synthesis of (3R)-3-amino-1,1-difluoroheptan-2-ol (90d)

To a solution of compound 90c (27.2 mg, 0.078 mmol) in EtOH (1 mL) wasadded 20% palladium hydroxide on carbon (15.9 mg, 0.023 mmol). Theresulting mixture was stirred under H₂ atmosphere for 20 h. The reactionmixture was then filtered and washed with EtOH (5 mL). The filtrate wasconcentrated in vacuo to obtain compound 90d. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₇H₁₁₆F₂NO: 168.12; found: 167.94; t_(R)=0.49 min onLC/MS Method A.

Synthesis of(3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1,1-difluoroheptan-2-ol(90e)

To a solution of compound 90d (12.4 mg, 0.074 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (11.8 mg, 0.059 mmol) in THF (1 mL)was added N,N-diisopropylethylamine (0.039 mL, 0.222 mmol). The mixturewas stirred for 2 h at rt, then additional THF (1 mL),N,N-diisopropylethylamine (0.039 mL, 0.222 mmol), and2,4-dimethoxybenzylamine (0.056 mL, 0.371 mmol) were added, and theresulting mixture heated to 100° C. for 20 h. The reaction mixture wascooled to rt, diluted with EtOAc (˜20 mL), washed with water (20 mL×3)and brine (20 mL×1), dried (MgSO₄), filtered and concentrated in vacuo.The residue was subjected to silica gel chromatography eluting with0-100% EtOAc in hexanes to isolate impure 90e. The impure material wasthen subjected to preparative HPLC purification (column, Gemini 10u C18110A, AXIA; 10% aq. acetonitrile-80% aq. acetonitrile with 0.1% TFA,over 20 min. gradient) to afford compound 90e LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₂₃H₃₀F₂N₅O₃: 462.23; found: 462.17; t_(R)=1.00 min onLC/MS Method A.

Synthesis of(3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1,1-difluoroheptan-2-ol(90)

Compound 90e (16 mg, 34.67 umol) was dissolved in TFA (1 mL) and stirredat rt. After 1 h, the mixture was concentrated in vacuo, and the residuewas triturated in methanol (1 mL×3), filtered, and diluted with water(˜6 mL). The mixture was subjected to preparative HPLC (Gemini 10u C18110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA,over 20 min. gradient). Collected product fractions were concentrated invacuo, co-evaporated with methanol (10 mL×3) and dried in vacuo toobtain compound 90 as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64(dd, J=4.3, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.78 (dd, J=8.5,4.3 Hz, 1H), 5.73 (td, J=55.6, 4.9 Hz, 1H), 4.70 (t, J=7.4 Hz, 1H),3.98-3.82 (m, 1H), 1.90-1.72 (m, 2H), 1.54-1.31 (m, 4H), 1.00-0.82 (m,3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.78, −129.57 (ddd, J=289.8,55.1, 8.6 Hz), −132.42 (ddd, J=290.1, 56.0, 12.5 Hz). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₁₄H₂₀F₂N₅O: 312.16; found: 312.15; t_(R)=0.74 minon LC/MS Method A.

Example 91

Synthesis of (3R)-3-amino-1-fluoroheptan-2-ol (91a)

A mixture of compound 88b (300.1 mg, 0.911 mmol) and 20% palladiumhydroxide on carbon (30.9 mg) in EtOH (5 mL) was stirred under H₂. Thereaction mixture was stirred for 20 h, filtered, and the solids werewashed with EtOH (10 mL). The filtrate was concentrated in vacuo and theresidue was co-evaporated with toluene (10 mL×2) to obtain compound 91a.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₇H₁₇FNO: 150.13; found: 149.95;t_(R)=0.47 min on LC/MS Method A.

Synthesis of(3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(91b)

A solution of 91a (133.7 mg, 0.896 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (201.6 mg, 1.008 mmol) in THF (6 mL)was treated with N,N-diisopropylethylamine (0.48 mL, 2.756 mmol). Themixture was stirred at rt for 2.75 h. The reaction mixture wasconcentrated in vacuo, and the residue was subjected to silica gelchromatography eluting with 20-70% EtOAc in hexanes to obtain, afterremoval of solvent in vacuo, compound 91b. LCMS-ESI⁺ (m/z): [M+H-C₂H₄]⁺calculated for C₁₄H₁₉ClFN₄O: 313.12; found: 313.14; t_(R)=1.04 min onLC/MS Method A.

Synthesis of(3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(91c)

To a solution of compound 91b (233.6 mg, 0.747 mmol) in dioxane (7 mL)was added N,N-diisopropylethylamine (0.64 mL, 3.674 mmol), and2,4-dimethoxybenzylamine (0.45 mL, 2.995 mmol). The resulting solutionwas refluxed at 110° C. bath for 24 h. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in DCM (30 mL), andwashed with water (30 mL×1). The aqueous fraction was extracted with DCM(30 mL×1), and the organic fractions were combined, dried (MgSO₄),filtered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with 20-100% EtOAc in hexanes. The collectedfractions were concentrated under reduced pressure and the residue wassubjected to preparative HPLC (Gemini 10u C18 110A, AXIA; 10% aq.acetonitrile-80% aq. acetonitrile with 0.1% TFA, over 20 min. gradient).The collected product fractions were combined, neutralized by saturatedaqueous NaHCO₃ solution (1 mL), partially concentrated in vacuo toremove acetonitrile and then extracted with EtOAc (20 mL×2). The organicextracts were washed with water (20 mL), combined, dried over MgSO₄,filtered and concentrated in vacuo to obtain compound 91c. LCMS-ESI⁺(m/z): [M+H-C₂H₄]⁺ calculated for C₂₃H₃₁FN₅O₃: 444.24; found: 444.19;t_(R)=0.97 min on LC/MS Method A.

Synthesis of2-((3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-yl)isoindoline-1,3-dione(91d)

To a solution of compound 91c (654 mg, 1.475 mmol), phthalimide (347.1mg, 2.359 mmol), and triphenylphosphine (874.8 mg, 3.359 mmol) in THF(24 mL) at 0° C. was added diisopropyl azodicarboxylate (0.697 mL, 3.539mmol). The reaction mixture was warmed to rt and stirred for 2 h. Afterthe reaction mixture was concentrated under reduced pressure, theresidue was subjected to silica gel chromatography eluting with 0-100%EtOAc in hexanes to obtain, after removal of volatiles in vacuo,compound 91d. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₃₁H₃₄FN₆O₄:573.26; found: 573.20; t_(R)=1.27 min on LC/MS Method A.

Synthesis ofN⁴-((3R)-2-amino-1-fluoroheptan-3-yl)-N²-(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine-2,4-diamine(91e)

To a solution of compound 91d (489.3 mg, 0.854 mmol) in EtOH (5 mL) wasadded hydrazine hydrate (0.07 mL, 1.28 mmol) at rt. The reaction mixturewas refluxed for 3.5 h, the precipitates were removed by filtration andthen the solid washed with EtOH (15 mL). The filtrates were concentratedin vacuo and the residue was dissolved in DCM (30 mL), washed with water(30 mL×2), dried over MgSO₄, filtered and concentrated in vacuo toobtain compound 91e. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₃₂FN₆O₂:443.26; found: 443.20; t_(R)=0.79 min on LC/MS Method A.

Synthesis ofN-((3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-yl)acetamide(91f)

To a solution of 91e (395.3 mg, 0.893 mmol) andN,N-diisopropylethylamine (0.311 mL, 1.787 mmol) in THF (8 mL) was addedacetic anhydride (0.127 mL, 1.340 mmol), and the reaction was stirredfor 30 min. at rt. The mixture was then diluted with EtOAc (30 mL),washed with saturated aqueous NaHCO₃ solution (30 mL), brine (30 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography eluting with 0-100%EtOAc in hexanes, followed by elution with 0-20% methanol in EtOAc. Thecollected product fractions were concentrated in vacuo and thensubjected to preparative HPLC purification (Gemini 10u C18 110A, AXIA;10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min.gradient) to obtain, after removal of volatiles in vacuo, compound 91f.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₅H₃₄FN₆O₃: 485.27; found:485.23; t_(R)=1.28 min on LC/MS Method A.

Synthesis ofN-((3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-yl)acetamide(91)

Compound 91f (50 mg, 0.103 mmol) was dissolved in TFA (3 mL) and stirredat rt for 11 h. The mixture was concentrated under reduced pressure, andthe residue was triturated with methanol (1 mL×3). After the insolublematerial was removed by filtration and the filtrate was diluted withwater (3 mL), the resulting solution was subjected to preparative HPLC(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient). Product-containing fractions werecombined, concentrated under reduced pressure to dryness, co-evaporatedwith methanol (×3), and finally dried under high vacuum to provide 91 asits TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.67 (ddd, J=4.3, 1.4, 0.6Hz, 1H), 7.96-7.69 (m, 2H), 4.82-4.67 (m, 1H), 4.60 (d, J=5.1 Hz, 1H),4.48 (d, J=5.0 Hz, 1H), 4.41 (dq, J=21.7, 5.1 Hz, 1H), 1.96 (d, J=4.2Hz, 3H), 1.78 (td, J=8.6, 4.6 Hz, 1H), 1.48-1.24 (m, 4H), 0.90 (tt,J=5.5, 2.3 Hz, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₆H₂₇FN₆O:335.19; found: 335.19; t_(R)=0.82 min on LC/MS Method A.

Example 92

Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-2-methylhexanoate(92b)

To a suspension of (S)-2-amino-2-methylhexanoic acid 92a (2018.9 mg,11.11 mmol, Asiba Pharmatech Inc.) in methanol (30 mL) was added thionylchloride (1.62 mL) dropwise, and the resulting solution was refluxed for41 h. The solution was concentrated under reduced pressure and theresidue was co-evaporated with methanol (30 mL×2). The residue wastreated with NaHCO₃ (4.6964 g, 55.90 mmol) in water (30 mL) and methanol(5 mL) and was stirred at rt. Di-tert-butyl dicarbonate (2932 mg, 13.43mmol) was added and the mixture stirred for 4 h. Additional NaHCO₃(1014.6 mg, 12.08 mmol) and di-tert-butyl dicarbonate (1234.0 mg, 5.654mmol) were then added and the resulting suspension was stirred at rtovernight. The reaction mixture was then diluted with water (100 mL) andextracted with EtOAc (100 mL×2). The organic extracts were washed withwater (100 mL), then combined, dried over MgSO₄ filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with 0-20% EtOAc in hexanes to obtain compound92b. LCMS-ESI⁺ (m/z): [M+H-C₄H₈]⁺ calculated for C₉H₁₈NO₄: 204.12;found: 203.68; t_(R)=1.24 min on LC/MS Method A.

Synthesis of (S)-tert-butyl (1-hydroxy-2-methylhexan-2-yl)carbamate(92c)

To a stirred solution of compound 92b (2515.4 mg, 9.699 mmol) in THF (20mL) and methanol (2.8 mL) at 0° C., was added 2.0 M LiBH₄ in THF (9.7mL, 19.4 mmol). The solution was stirred at rt for 5 h, was and thendiluted with water (100 mL) at 0° C., and extracted with EtOAc (100mL×2). The combined extracts were washed with water (100 mL), dried overMgSO₄, filtered and concentrated in vacuo. The residue was subjected tosilica gel chromatography eluting with 0-40% EtOAc in hexanes to providecompound 92c LCMS-ESI⁺ (m/z): [M+H-C₄H₈]calculated for C₁₂H₂₆NO₃:232.19; found: 231.60; t_(R)=1.07 min on LC/MS Method A.

Synthesis of (S)-tert-butyl (2-methyl-1-oxohexan-2-yl)carbamate (92d)

To a solution of compound 92c (543.3 mg, 2.349 mmol) in DCM (20 mL) wasadded Dess-Martin Periodinane (1495.1 mg, 3.525 mmol) and the resultingmixture stirred for 3 h. The reaction mixture was diluted with DCM (30mL) and filtered through a pad of Celite. The filtrate was washed withsaturated aqueous Na₂S₂O₃ (50 mL), water (50 mL), and brine (50 mL). Theaqueous fraction was re-extracted with DCM (30 mL×2), and the combinedorganic fractions were dried over Na₂SO₄, filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith 0-70% EtOAc in hexanes to obtain compound 92d. LCMS-ESI⁺ (m/z):[M+H-C₄Hs]⁺ calculated for C₈H₁₆NO₃: 174.11; found: 174.76, t_(R)=1.28min on LC/MS Method A.

Synthesis of tert-butyl ((3S)-2-hydroxy-3-methylheptan-3-yl)carbamate(92e)

To a solution of compound 92d (511.8 mg, 2.232 mmol) in diethyl ether (5mL) cooled in an ice-salt bath (−15° C.), was added 1.6 M solution ofMeLi in diethyl ether (5.58 mL, 8.927 mmol) dropwise over 5 min. After30 min, the reaction mixture was quenched with saturated aqueous NH₄Clsolution (15 mL). The resulting mixture was diluted with water and theproduct was extracted with EtOAc (25 mL×2). The combined extracts weredried over MgSO₄, filtered and concentrated in vacuo. The residue wasthen subjected to silica gel chromatography eluting with 0-70% EtOAc inhexanes to provide compound 92e as a mixture of two diastereomers.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₃H₂₈NO₃: 246.21; found: 245.63;t_(R)=1.28 min on LC/MS Method A.

Synthesis of(3S)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(92f)

Compound 92e (347 mg, 1.414 mmol) was dissolved in 4M HCl in dioxane(3.1 mL) and stirred at rt for 4 h. The reaction mixture was thenconcentrated in vacuo. The residue in THF (10.5 mL) was treated with2,4-dichloropyrido[3,2-d]pyrimidine (259.1 mg, 1.295 mmol) andN,N-diisopropylethylamine (1.18 mL, 6.77 mmol), and placed in 80° C.bath for 1 h. The reaction mixture was cooled to rt, concentrated underreduced pressure, and the residue subjected to silica gel chromatographyeluting with 0-70% EtOAc in hexanes to obtain compound 92f. LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₅H₂₁C₁N₄O: 309.15; found: 309.12;t_(R)=1.32 min on LC/MS Method A.

Synthesis of(2R,3S)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-oland(2S,3S)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(92g and 92h)

To a solution of compound 92f (331.8 mg, 1.074 mmol) in dioxane (11 mL)was added N,N-diisopropylethylamine (0.561 mL, 3.223 mmol) and2,4-dimethoxybenzylamine (0.807 mL, 5.372 mmol). The resulting mixturewas refluxed at 110° C. bath for 17 h. The mixture was then concentratedin vacuo and the resulting residue dissolved in EtOAc (50 mL) and washedwith water (50 mL×2) and brine (50 mL). The organic fraction was driedover Na₂SO₄, filtered and then concentrated in vacuo. The resultingresidue was subjected to silica gel chromatography eluting with 0-100%EtOAc in hexanes. The collected product was then concentrated in vacuoand resubjected to column chromatography on silica gel eluting with0-20% MeOH in DCM to obtain a mixture of compound 92g and 92h. Themixture was then concentrated in vacuo and the residue subjected topreparative chiral SFC (SFC IC-5 um-4.6×100 mm, 40% EtOH-ammonia) toobtain after removal of volatiles in vacuo compound 92g eluting first,and compound 92h eluting second.

Compound 92g: ¹H NMR (400 MHz, Chloroform-d) δ 8.29 (dd, J=4.5, 1.5 Hz,1H), 7.71 (d, J=8.4 Hz, 1H), 7.44 (dd, J=8.5, 4.3 Hz, 1H), 7.29 (d,J=8.2 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.2, 2.4 Hz, 1H),4.56 (d, J=5.8 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.13 (t, J=12.7 Hz,1H), 1.88 (t, J=11.5 Hz, 1H), 1.45 (ddd, J=12.9, 9.7, 5.5 Hz, 1H), 1.38(s, 3H), 1.35-1.22 (m, 2H), 1.21 (d, J=6.3 Hz, 4H), 0.87 (t, J=7.2 Hz,3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₄H₃₄N₅O₃: 440.27; found:440.18; t_(R)=1.29 min on LC/MS Method A.

Compound 92h: ¹H NMR (400 MHz, Chloroform-d) δ 8.29 (dd, J=4.3, 1.5 Hz,1H), 7.70 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.5, 4.3 Hz, 1H), 7.29 (d,J=8.2 Hz, 1H), 7.20 (s, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.2,2.4 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.97(d, J=10.6 Hz, 1H), 1.59 (dt, J=13.9, 7.2 Hz, 1H), 1.48 (s, 3H), 1.36(qd, J=7.2, 6.7, 4.0 Hz, 4H), 1.26 (d, J=1.4 Hz, 1H), 1.18 (d, J=6.4 Hz,3H), 0.97-0.90 (m, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₄H₃₄N₅O₃: 440.27; found: 440.18; t_(R)=1.28 min on LC/MS Method A.

Synthesis of(3S)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(92)

Compound 92g (74.1 mg, 0.169 mmol) was dissolved in TFA (3 mL) andstirred at rt for 0.75 h. The reaction mixture was carefullyconcentrated under reduced pressure to dryness. The residue wastriturated with 50% aq. methanol and filtered through a Celite-membranefilter. The filtrate was then subjected to preparative HPLC (Gemini 10uC18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA,over 20 min. gradient). The product fractions were combined,concentrated in vacuo, then co-evaporated with methanol (10 mL×3), anddried under vacuum to provide compound 92 as its TFA salt. ¹H NMR (400MHz, Methanol-d₄) δ 8.61 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.36 (q, J=6.5 Hz, 1H), 2.30 (dt,J=16.4, 6.8 Hz, 1H), 1.91-1.78 (m, 1H), 1.56 (s, 3H), 1.46-1.29 (m, 4H),1.23 (d, J=6.5 Hz, 3H), 0.97-0.85 (m, 3H). ¹⁹F NMR (376 MHz,Methanol-d₄) δ −77.60. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₅H₂₄N₅O:290.20; found: 290.14; t_(R)=0.82 min on LC/MS Method A.

Example 93

Synthesis of (4R)-ethyl4-phenyl-2-(trifluoromethyl)oxazolidine-2-carboxylate (93c)

A solution of (R)—N-Boc-phenylglycinol 93a (522.4 mg, 2.249 mmol,Combi-Blocks, Inc.), ethyl trifluoropyruvate 93b (0.328 mL, 2.474 mmol,Oakwood Products), and pyridinium p-toluenesulfonate (113.1 mg, 0.450mmol) in toluene (20 mL) was refluxed with a Dean-Stark apparatus for 20h. The reaction mixture was then cooled to 0° C. using an ice-water bathand filtered through a pad of Celite. After the filtrate wasconcentrated in vacuo, the residue was subjected to silica gelchromatography eluting with 0-30% EtOAc in hexanes to obtain compound93c. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₃H₁₅F₃NO₃: 290.10; found:289.84; t_(R)=1.21 min on LC/MS Method A.

Synthesis of ((4R)-4-phenyl-2-(trifluoromethyl)oxazolidin-2-yl)methanol(93d)

To a solution of compound 93c (384.9 mg, 1.331 mmol) in MeOH (6 mL) at0° C. was added sodium borohydride (50.3 mg, 1.331 mmol). The reactionmixture was warmed to rt and stirred for 30 min. before quenching withaqueous saturated NH₄Cl (15 mL). After methanol was removed underreduced pressure, the resulting aqueous solution was extracted withEtOAc (25 mL×3). The organic extracts were washed with water (25 mL×2)and brine (25 mL), combined, dried over MgSO₄, filtered and thenconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with 0-40% EtOAc in hexanes to obtain compound93d LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₁H₁₃F₃NO₂: 248.09; found:247.90; t_(R)=0.96 min on LC/MS Method A.

Synthesis of(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(trifluoromethyl)hexan-1-ol(93e)

To a solution of compound 93d (264.7 mg, 1.071 mmol) in THF (13 mL) at−78° C. was added n-butyllithium (2.5 M in hexane, 1.713 mL, 4.283 mmol)dropwise. The resulting solution was stirred in a cold bath for 2 hbefore quenching with aqueous saturated NH₄Cl (30 mL). The mixture wasextracted with EtOAc (30 mL×3) and the extracts were washed with water(30 mL×2) and brine (30 mL×1). The organic fractions were combined,dried over MgSO₄, filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with 0-70% EtOAc inhexanes to obtain compound 93e LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₁₅H₂₃F₃NO₂: 306.17; found: 305.90, t_(R)=1.13 min on LC/MS Method A.

Synthesis of (R)-2-amino-2-(trifluoromethyl)hexan-1-ol hydrochloride(93f)

To a solution of compound 93e (146.5 mg, 0.480 mmol) in EtOH (1 mL) andconcentrated HCl (0.3 mL) was added palladium hydroxide on carbon (67.4mg) and the resulting mixture was stirred under H₂ atmosphere for 24 h.The reaction mixture was filtered through a pad of Celite and then thesolids rinsed with EtOH (25 mL). The eluants were concentrated underreduced pressure, diluted with water (20 mL) and then extracted withEtOAc (20 mL×2). The organic extracts were combined and concentratedunder reduced pressure to obtain of compound 93f as its HCl salt.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₇H15F₃NO: 186.11; found: 185.95;t_(R)=0.51 min on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-(trifluoromethyl)hexan-1-ol(93h)

To a solution of compound 93f (123.84 mg, 0.480 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (96.0 mg, 0.480 mmol) in THF (4 mL)was added N,N-diisopropylethylamine (0.251 mL, 1.439 mmol). The reactionmixture was stirred and heated to 80° C. for 18 h. The reaction mixturewas allowed to cool and concentrated in vacuo. The resulting residue wassubjected to silica gel chromatography eluting with 0-100% EtOAc inhexanes to afford compound 93g (109.9 mg, 66%). To a solution ofcompound 93g (109.9 mg, 0.315 mmol) in dioxane (3.5 mL) was addedN,N-diisopropylethylamine (0.165 mL, 0.945 mmol) and2,4-dimethoxybenzylamine (0.237 mL, 1.576 mmol). The mixture wasrefluxed at 110° C. for 20 h, allowed to cool to rt, diluted with EtOAc(30 mL), washed with water (30 mL×3) and brine (30 mL), dried overMgSO₄, filtered and concentrated in vacuo. The resulting residue wassubjected to silica gel chromatography eluting with 0-100% EtOAc inhexanes. The collected fractions were concentrated in vacuo to a residuethat was subjected to preparative HPLC purification (Gemini 10u C18110A, AXIA; 10% aq. acetonitrile-80% aq. acetonitrile with 0.1% TFA,over 20 min. gradient) to afford compound 93h LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₂₃H₂₉F₃N₅O₃: 480.22; found: 480.17; t_(R)=0.96 min onLC/MS Method A.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-(trifluoromethyl)hexan-1-ol(93)

Compound 93h (7.8 mg, 16.27 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was then concentrated invacuo and the residue was co-evaporated with methanol (5 mL×3). Theresidue was triturated with 50% aq. methanol and filtered through aCelite-membrane filter. The filtrate was subjected to preparative HPLC(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient). The product fractions werecombined, concentrated under reduced pressure, co-evaporated withmethanol (10 mL×3), and dried under vacuum to provide compound 93 as itsTFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.67 (dd, J=4.4, 1.4 Hz, 1H),7.89 (dd, J=8.5, 1.4 Hz, 1H), 7.82 (dd, J=8.5, 4.4 Hz, 1H), 4.11 (d,J=12.2 Hz, 1H), 4.06-3.97 (m, 1H), 2.81 (ddd, J=13.8, 11.0, 4.4 Hz, 1H),1.99-1.85 (m, 1H), 1.38 (m, 4H), 0.92 (t, J=7.0 Hz, 3H). ¹⁹F NMR (376MHz, Methanol-d4) δ −75.96 (s, 3F), −77.39 (s, 3F). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₁₄H₁₉F₃N₅O: 330.15; found: 330.16; t_(R)=0.76 minon LC/MS Method A.

Example 94

Synthesis of (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (94c)and 3-methyl-5-phenyl-3,6-dihydro-2H-1,4-oxazin-2-one (94d)

To a mixture of (R)-(−)-2-phenylglycinol 94a, (Sigma-Aldrich, 98%, 99%ee, 3.6296 g, 172.25 mmol) and molecular sieves (86.03 g) in2,2,2-trifluoroethanol (500 mL) was added ethyl pyruvate 94b (19.2 mL,172.29 mmol) and the resulting mixture heated to reflux temperature.After 24 h, the mixture was cooled to rt, filtered through a pad ofCelite, and washed with EtOAc (50 mL). The orange filtrate and the EtOAcwashes were separated into two flasks and each was concentrated underreduced pressure. Each of the resulting residues was subjected to silicagel chromatography eluting with 0-40% EtOAc in hexanes. Productfractions from the two chromatography's were combined, concentratedunder reduced pressure, and dried in vacuo to provide compound 94c aswell as the later eluting compound 94d.

Compound 94c: ¹H NMR (400 MHz, Chloroform-d) δ 7.45-7.38 (m, 2H),7.38-7.32 (m, 3H), 4.85 (ddd, J=10.9, 4.6, 2.4 Hz, 1H), 4.57 (dd,J=11.6, 4.5 Hz, 1H), 4.26 (dd, J=11.6, 10.9 Hz, 1H), 2.41 (d, J=2.4 Hz,3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₁H₁₂NO₂: 190.09; found:189.92; t_(R)=0.88 min on LC/MS Method A.

Compound 94d: ¹H NMR (400 MHz, Chloroform-d) δ 7.81-7.71 (m, 2H),7.55-7.41 (m, 3H), 5.47 (dd, J=16.0, 1.2 Hz, 1H), 5.25 (dd, J=16.0, 2.8Hz, 1H), 4.31 (qdd, J=7.1, 3.0, 1.1 Hz, 1H), 1.72 (d, J=7.3 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₁H₁₂NO₂: 190.09; found: 189.94;t_(R)=0.83 min on LC/MS Method A.

Synthesis of (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one (94e)

A solution of compound 94c (14.84 g, 78.43 mmol) in THF (500 mL) wasstirred at −78° C. bath under argon and boron trifluoride diethyletherate (20.5 mL, 161.11 mmol) was added slowly over 30 min. Thereaction mixture was allowed to stir at −78° C. for 1.5 h. 2Mbutylmagnesium chloride solution 2.0 M in THF (83.0 mL) was added slowlyover ˜30 min. and the reaction mixture was allowed to stir at −78° C.for 2h before addition of saturated ammonium chloride (300 mL) followedby warming to rt. The mixture was diluted with water (200 mL) andextracted with EtOAc (300 mL×3). The organic extracts were washed withwater (500 mL×3), brine (300 mL), combined, dried (Na₂SO₄), andconcentrated under reduced pressure. After the residue was dissolved inDCM (150 mL, heating), the insoluble material was removed by filtration.The filtrate was concentrated under reduced pressure to a small volume,and was subjected to silica gel chromatography eluting with 0-20% EtOAcin hexanes to provide compound 94e. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₅H₂₂NO₂: 248.17; found: 248.02; t_(R)=1.07 min on LC/MS Method A.

Synthesis of(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol (94f)

To a stirred solution of compound 94e (14.01 g, 56.64 mmol) in THF (100mL) at 0° C. was added 2.0 M LiBH₄ in THF (57 mL, 114 mmol). Thesolution was stirred at rt for 2 h, cooled with an ice bath and quenchedwith water (500 mL). The product was extracted with EtOAc (300 mL×3) andthe extracts were washed with water (500 mL) and brine (100 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated under reducedpressure to obtain 94f LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₅H₂₆NO₂:252.20; found: 252.05; t_(R)=0.68 min on LC/MS Method A.

Synthesis of (R)-2-amino-2-methylhexan-1-ol hydrochloride (94g)

To a mixture of compound 94f (14.24 g, 56.65 mmol) and 20% Pd(OH)₂ oncarbon (2.847 g) in EtOH (210 mL) was added 4 N HCl in dioxane (21.5 mL,86.0 mmol) The resulting mixture was purged with H₂ gas (3 times) andthen stirred under H₂ atmosphere at 70° C. for 8 h. The reaction mixturewas allowed to cool and additional 20% Pd(OH)₂ on carbon (0.71 g) wasadded. The resulting mixture was purged with H₂ gas (3 times) and thenstirred under H₂ atmosphere at 70° C. for 2 h. The reaction mixture wascooled and filtered through a Celite pad and the removed solids washedwith EtOH (50 mL). The filtrate and EtOH washings were combined andconcentrated under reduced pressure. The residue was co-evaporated withDCM (100 mL×3) and dried under vacuum to give compound 94g. The residuewas triturated with DCM (50 mL) and toluene (50 mL) and thenconcentrated under reduced pressure. The residue was co-evaporated withtoluene (50 mL×1) and dried under vacuum at 40° C. for 1 h, and rtovernight to obtain compound 94g as its HCl salt. LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₇H8NO: 132.14; found: 131.90; t_(R)=0.42 min onLC/MS Method A.

Synthesis of (R)-tert-butyl (1-hydroxy-2-methylhexan-2-yl)carbamate(94h)

To a solution of 94g (3.1403 g, 16.01 mmol) in methanol (7 mL) and water(45 mL) was added sodium bicarbonate (4.05 g, 48.21 mmol) anddi-tert-butyl dicarbonate (Boc₂O, 4.25 g, 19.47 mmol). The resultingmixture was stirred at rt for 3 h and then additional sodium bicarbonate(0.68 g, 8.095 mmol) and di-tert-butyl dicarbonate (1.752 g, 8.028 mmol)were added. The mixture was stirred for 48 h and then additional sodiumbicarbonate (0.808 g, 9.618 mmol) and di-tert-butyl dicarbonate (1.92 g,8.797 mmol) were added. The reaction mixture was stirred for 4 h,diluted with water (100 mL), and extracted with EtOAc (100 mL×2). Theextracts were washed with water (100 mL), dried over MgSO₄, filtered andthen concentrated under reduced pressure. The residue was subjected tosilica gel chromatography eluting with 0-40% EtOAc in hexanes to obtaincompound 94h LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₂H₂₆NO₃: 232.19;found: 231.65; t_(R)=1.08 min on LC/MS Method A.

Synthesis of (R)-tert-butyl (2-methyl-1-oxohexan-2-yl)carbamate (94i)

To a solution of compound 94h (446.7 mg, 1.931 mmol) in DCM (15 mL) wasadded Dess-Martin Periodinane (1230.6 mg, 2.901 mmol) and the resultingmixture was stirred for 3 h. The reaction mixture was filtered through apad of Celite, and the filtrate was then washed with saturated aqueousNa₂S₂O₃ (30 mL) followed by water (30 mL×2). The aqueous fractions wereback extracted with DCM (30 mL), and all the organic fractions were thencombined, dried over MgSO₄, filtered and concentrated in vacuo. Theresulting residue was subjected to silica gel chromatography elutingwith 0-30% EtOAc in hexanes to obtain compound 94i. LCMS-ESI⁺ (m/z):[M+H-C₄Hs]⁺ calculated for C₅H₁₆NO₃: 174.11; found: 173.77; t_(R)=1.17min on LC/MS Method A.

Synthesis of tert-butyl ((3R)-2-hydroxy-3-methylheptan-3-yl)carbamate(94j)

To a solution of compound 94i (322.4 mg, 1.406 mmol) in diethyl ether (5mL) in an ice-NaCl bath was added 1.6 M MeLi in diethyl ether (3.6 mL,5.76 mmol) dropwise over 2 min. After 30 min, the reaction mixture wasquenched with saturated aqueous ammonium chloride solution (20 mL). Thetwo phases were separated and the aqueous fraction was extracted withDCM (30 mL). The organic fractions were washed with water (30 mL),combined, dried over MgSO₄, filtered and then concentrated in vacuo. Theresidue was then subjected to silica gel chromatography eluting with0-40% EtOAc in hexanes to obtain compound 94j. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₃H₂₈NO₃: 246.21; found: 245.70; t_(R)=1.14 min. andt_(R)=1.16 min on LC/MS Method A.

Synthesis of(3R)-3-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(94k)

Compound 94j (119.8 mg, 0.488 mmol) was dissolved in 4M HCl in dioxane(3 mL) and stirred at rt for 1 h. The reaction mixture was concentratedin vacuo and the residue was then treated with THF (10.5 mL) followed by2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (110.9 mg, 0.508 mmol)and N,N-diisopropylethylamine (0.36 mL, 2.067 mmol). The mixture washeated in a 80° C. bath for 3 h. The reaction mixture was allowed tocool to rt, concentrated in vacuo and the residue subjected to silicagel chromatography eluting with 0-100% EtOAc in hexanes to obtaincompound 94k as a mixture of two diastereomers (˜2:3 ratio). ¹H NMR (400MHz, Chloroform-d) δ 8.55 (dd, J=2.6, 1.2 Hz, 1H), 7.66 (dd, J=8.8, 2.6Hz, 1H), 7.35 (d, J=10.9 Hz, 1H), 5.29 (br, 1H), 3.97 (q, J=6.1 Hz,0.4H), 3.91 (q, J=6.4 Hz, 0.6H), 2.09 (ddd, J=13.8, 12.3, 4.4 Hz, 0.6H),2.03-1.88 (m, 1H), 1.67 (dt, J=14.2, 7.0 Hz, 0.4H), 1.51 (s, 1.2H), 1.43(s, 1.8H), 1.49-1.136 (m, 4H), 1.22 (d, J=6.5 Hz, 1.8H), 1.20 (d, J=6.5Hz, 1.2H), 0.99-0.91 (m, 1.2H), 0.88 (t, J=7.3 Hz, 1.8H). ¹⁹F NMR (376MHz, Chloroform-d) 6-117.38 (t, J=8.9 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₅H₂₁ClFN₄O: 327.14; found: 327.11; t_(R)=1.23 min onLC/MS Method A.

Synthesis of(2R,3R)-3-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-oland(2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(941 and 94m)

To a solution of compound 94k (128.5 mg, 0.416 mmol) in dioxane (5 mL)was added N,N-diisopropylethylamine (0.22 mL, 1.263 mmol) and2,4-dimethoxybenzylamine (0.16 mL, 1.065 mmol) and the resulting mixturewas refluxed in a 110° C. bath for 20 h. The reaction mixture wasallowed to cool to rt, diluted with EtOAc (30 mL) and then washed withwater (30 mL×2). The aqueous fractions were then back extracted withEtOAc (30 mL). The organic fractions were combined, dried over MgSO₄,and concentrated under reduced pressure. The residue was then subjectedto silica gel chromatography eluting with 0-100% EtOAc in hexanes toobtain a mixture of compounds 941 and 94m. The compound mixture wasfurther subjected to preparative chiral SFC (SFC IC-5 um-4.6×100 mm, 30%EtOH-ammonia, flow rate=3 mL/min) to obtain, compound 941, elutingfirst, and compound 94m, eluting second.

Compound 941: ¹H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H),7.32 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd,J=8.3, 2.4 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H),4.0-3.7 (m, 1H), 1.97 (s, 1H), 1.59 (s, 2H), 1.47 (s, 3H), 1.36 (d,J=5.2 Hz, 4H), 1.17 (d, J=6.4 Hz, 3H), 1.00-0.89 (m, 3H). ¹⁹F NMR (376MHz, Chloroform-d) δ −121.41. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₄H₃₃FN₅O₃: 458.26; found: 458.17; t_(R)=1.19 min on LC/MS Method A.

Compound 94m: ¹H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J=2.6 Hz, 1H),7.33 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.42 (dd,J=8.3, 2.4 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 3.84 (d, J=1.1 Hz, 3H), 3.79(s, 3H), 3.9-3.6 (m, 1H), 2.09 (d, J=14.1 Hz, 1H), 1.87 (s, 1H), 1.57(s, 1H), 1.43 (m, 1H), 1.37 (s, 3H), 1.30 (m, 2H), 1.20 (d, J=6.4 Hz,3H), 0.87 (t, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −121.40.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₄H₃₃FN₅O₃: 458.26; found:458.16; t_(R)=1.22 min on LC/MS Method A.

Synthesis of(3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(94)

Compound 94m (9.0 mg, 20.5 umol) was dissolved in TFA (1 mL) and stirredat rt for 1 h. The reaction mixture was carefully concentrated underreduced pressure to dryness, and the residue was then triturated with50% aq. methanol, and filtered through a Celite-membrane filter. Thefiltrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA;10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min.gradient). The product fractions were combined, concentrated underreduced pressure, co-evaporated with methanol (10 mL×3), and dried undervacuum to obtain compound 94 as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.54 (d, J=2.4 Hz, 1H), 8.31 (s, 1H), 7.62 (dd, J=8.8,2.5 Hz, 1H), 4.39-4.29 (m, 1H), 2.29 (dt, J=15.7, 6.7 Hz, 1H), 1.84 (dt,J=16.0, 6.9 Hz, 1H), 1.55 (s, 3H), 1.44-1.30 (m, 4H), 1.23 (d, J=6.5 Hz,3H), 0.96-0.84 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.53 (s, 3F),−118.19 (dd, J=8.8, 4.0 Hz, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₁₅H₂₃FN₅O: 308.19; found: 308.12; t_(R)=1.46 min on LC/MS Method A.

Example 95

Synthesis of(2R,3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(95)

Compound 941 (10.3 mg, 23.4 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. After the reaction mixture was carefullyconcentrated to dryness in vacuo, the residue was triturated with 50%aq. methanol and filtered through Celite-membrane filter. The filtratewas subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient).The product fractions were combined, concentrated under reducedpressure, co-evaporated with methanol (10 mL×3), and dried under vacuumovernight to obtain compound 95 as its TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.53 (d, J=2.4 Hz, 1H), 8.41 (s, 1H), 7.62 (dd, J=8.7,2.5 Hz, 1H), 4.24 (q, J=6.4 Hz, 1H), 2.14 (ddd, J=15.0, 11.3, 4.2 Hz,1H), 2.04 (dq, J=14.3, 5.2 Hz, 1H), 1.48 (s, 3H), 1.39-1.24 (m, 4H),1.22 (d, J=6.4 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H). ¹⁹F NMR (376 MHz,Methanol-d₄) δ −77.52 (s, 3F), −118.31 (dd, J=8.7, 4.1 Hz, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₅H₂₃FN₅O: 308.19; found:308.12; t_(R)=1.47 min on LC/MS Method A.

Example 96

Synthesis of(3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(96a)

Compound 94j (195.7 mg, 0.798 mmol) was dissolved in 4M HCl in dioxane(3 mL) and stirred at rt for 1 h. The reaction mixture was thenconcentrated in vacuo. The residue was treated with2-methyltetrahydrofuran (5 mL), 2,4-dichloropyrido[3,2-d]pyrimidine (160mg, 0.525 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.272 mmol) andheated with an 80° C. bath for 3 h. The reaction mixture was cooled tort, concentrated under reduced pressure and the residue was subjected tosilica gel chromatography eluting with 0-100% EtOAc in hexanes to obtaincompound 96a as a mixture of two diastereomers (˜2:3 ratio). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₅H₂₂ClN₄O: 309.15; found: 309.08; TR=1.41min on LC/MS Method A.

Synthesis of(2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-oland(2R,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(96b and 96c)

To a solution of compound 96a (132.6 mg, 0.429 mmol) in dioxane (5 mL)was added N,N-diisopropylethylamine (0.23 mL, 1.320 mmol) and2,4-dimethoxybenzylamine (0.16 mL, 1.065 mmol), and the resultingmixture refluxed at 110° C. for 20 h. The reaction mixture was dilutedwith EtOAc (30 mL) and washed with water (30 mL×2). The aqueousfractions were back extracted with EtOAc (50 mL). The organic fractionswere combined, dried over MgSO₄, filtered and then concentrated underreduced pressure. The residue was subjected to silica gel chromatographyeluting with 0-100% EtOAc in hexanes to obtain a mixture of compounds96b and 96c. The mixture was further subjected to chiral SFC (SFC IC-5um-4.6×100 mm, 40% EtOH-ammonia, flow rate=3 mL/min) to obtain compound96b, eluting first, and compound 96c, eluting second.

Compound 96b: ¹H NMR (400 MHz, Chloroform-d) δ 8.28 (dd, J=4.2, 1.5 Hz,1H), 7.69 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.5, 4.3 Hz, 1H), 7.29 (d,J=8.2 Hz, 1H), 7.19 (s, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.2,2.4 Hz, 1H), 5.3 (br, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.86 (m, 1H), 3.83(s, 3H), 3.79 (s, 3H), 1.98 (m, 1H), 1.66-1.53 (m, 1H), 1.48 (s, 3H),1.44-1.30 (m, 4H), 1.17 (d, J=6.4 Hz, 3H), 0.98-0.89 (m, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₂₄H₃₄N₅O₃: 440.27; found: 440.25; TR=0.99min on LC/MS Method A.

Compound 96c: ¹H NMR (400 MHz, Chloroform-d) δ 8.29 (dd, J=4.2, 1.5 Hz,1H), 7.70 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.5, 4.2 Hz, 1H), 7.30 (d,J=8.2 Hz, 1H), 7.16 (s, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.42 (dd, J=8.2,2.4 Hz, 1H), 5.25 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.84 (s, 3H), 3.79(s, 3H), 3.86-3.75 (m, 1H), 2.13 (t, J=13.0 Hz, 1H), 1.93-1.79 (m, 1H),1.52-1.40 (m, 1H), 1.38 (s, 3H), 1.35-1.15 (m, 3H), 1.20 (d, J=6.4 Hz,3H), 0.87 (t, J=7.2 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₄H₃₄N₅O₃: 440.27; found: 440.25; t_(R)=1.00 min on LC/MS Method A.

Synthesis of(3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(96)

Compound 96b (8.7 mg, 19.79 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was concentrated underreduced pressure to dryness and then co-evaporated with methanol (10mL). The resulting residue was dissolved in methanol (1 mL) andconcentrated ammonium hydroxide (0.1 mL). The reaction mixture wasstirred for 10 min. and then concentrated under reduced pressure todryness and co-evaporated with methanol (10 mL). The residue wastriturated with 50% aq. MeOH (10 mL) and filtered through aCelite-membrane filter. The filtrate was subjected to preparative HPLC(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient). The product fractions werecombined, concentrated in vacuo, co-evaporated with methanol (10 mL×3),and dried under high-vacuum to provide compound 96 as its TFA salt. ¹HNMR (400 MHz, Methanol-d4) δ 8.61 (dd, J=4.4, 1.5 Hz, 1H), 7.82 (dd,J=8.5, 1.5 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.36 (q, J=6.5 Hz,1H), 2.30 (dt, J=16.3, 6.8 Hz, 1H), 1.91-1.78 (m, 1H), 1.56 (s, 3H),1.43-1.30 (m, 4H), 1.23 (d, J=6.5 Hz, 3H), 0.98-0.85 (m, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₅H₂₄N₅O: 290.20; found: 290.11;t_(R)=0.74 min on LC/MS Method A.

Example 97

Synthesis of(3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol(97)

Compound 96c (9.0 mg, 20.5 umol) was dissolved in TFA (1 mL) and stirredat rt for 1 h. The reaction mixture was carefully concentrated underreduced pressure to dryness and co-evaporated with methanol (10 mL). Theresidue was dissolved in methanol (1 mL) and concentrated ammoniumhydroxide (0.1 mL). The reaction mixture was stirred for 10 min. andthen concentrated under reduced pressure to dryness and thenco-evaporated with methanol (10 mL). The resulting residue wastriturated with 50% aq. methanol and filtered through a Celite-membranefilter. The filtrate was then subjected to preparative HPLC (Gemini 10uC18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA,over 20 min. gradient). The product fractions were combined,concentrated under reduced pressure, co-evaporated with methanol (10mL×3), and dried under high-vacuum to provide compound 97 as its TFAsalt. ¹H NMR (400 MHz, Methanol-d4) δ 8.61 (dd, J=4.3, 1.3 Hz, 1H), 7.82(dd, J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5, 4.3 Hz, 1H), 4.26 (q, J=6.4Hz, 1H), 2.11 (dddd, J=24.9, 19.8, 12.8, 7.0 Hz, 2H), 1.49 (s, 3H),1.40-1.24 (m, 4H), 1.22 (d, J=6.4 Hz, 3H), 0.89 (t, J=6.9 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₅H₂₄N₅O: 290.20; found: 290.10;t_(R)=0.74 min on LC/MS Method A.

Example 98

Synthesis of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(98)

Intermediate 43B (101 mg, 0.56 mmol) and (R)-a-Me-norleucinol 59A (109mg, 0.83 mmol) were added to NMP (5.5 mL) followed by BOP reagent (0.36g, 0.83 mmol) and DBU (0.25 mL, 1.67 mmol). The reaction mixture wasstirred at rt for 16 h, and then diluted with EtOH (2 mL) and water (2mL). The resulting mixture was subjected directly to HPLC purification(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-80% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient) to provide, after collection ofproduct fractions and removal of solvent in vacuo, compound 98 as a TFAsalt. ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J=2.4 Hz, 1H), 8.22 (s,1H), 7.64 (dd, J=8.7, 2.5 Hz, 1H), 3.97 (d, J=11.2 Hz, 1H), 3.71 (d,J=11.2 Hz, 1H), 2.09 (m, 1H), 1.92 (m, 1H), 1.54 (s, 3H), 1.40-1.31 (m,4H), 1.00-0.85 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.68, −118.20(d, J=8.8 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₀FN₅O:293.34; found: 294.1; t_(R)=0.68 min.

Example 99

Synthesis of (3R,5R,6S)-tert-butyl2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate(99a)

Imidazole (1.75 g, 0.03 mol), and triphenylphosphine, 99+% (6.08 g, 0.02mol) were stirred in DCM (100 mL) under argon and cooled to 0° C. for 10minutes. Iodine (5.94 g, 0.02 mol) was added over 5 minutes and thereaction was stirred at 0° C. for 20 minutes. A solution of4,4,4-trifluoro-1-butanol, 97% (2.48 mL, 0.02 mol) was slowly added. Thereaction was stirred and allowed to warm to rt. After 16 h, pentane (200mL) was added and the resulting solids filtered off. Solvent waspartially removed under reduced pressure, and then additional coldpentane (50 mL) was added. The solids were filtered off and the eluentconcentrated under reduced pressure to afford1,1,1-trifluoro-4-iodobutane.

(2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate, 72A (1 g,2.83 mmol) and 1,1,1-trifluoro-4-iodobutane (2.02 g, 8.49 mmol) weredissolved in THF (24 mL) and HMPA (2.5 mL), and the mixture was thencooled to −78° C. under argon. 1M lithium hexamethyldisilazide (1.0M THFin THF, 4.24 mL) was added and the reaction transferred to a −40° C.bath. The cold bath was recharged with dry ice and the reaction left towarm to ambient temperature with stirring overnight. The reaction wasquenched with EtOAc (25 mL) and poured into a mixture of EtOAc (100 mL)and saturated aqueous solution of NH₄Cl (50 mL). The organic layer wasseparated and washed with water (100 mL), brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography eluting with hexanes-EtOAc toprovide (3R,5R,6S)-tert-butyl2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate 99a.

Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohexanoicacid (99b)

Lithium (granular), (157.24 mg, 22.65 mmol) was cooled in a −40° C.bath. Ammonia gas was slowly condensed via a cold finger into thereaction for 15-20 minutes. After an additional 20minutes(3R,5R,6S)-tert-butyl2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate, 99a(700 mg, 1.51 mmol) in THF (10 mL) and EtOH (0.5 mL) was added. Thereaction was allowed to warm to rt, and the liquid ammonia allowed toevaporate with stirring overnight. The resulting residue was treatedwith THF (50 mL) and water (50 mL) and stirred until all the solidsdissolved. A saturated aq. ammonium chloride (50 mL) solution was addedfollowed by 1N NaOH to adjust the pH to basic. The reaction mixture waswashed with diethyl ether (100 mL), and the aqueous layer was then pHadjusted with 1N HCl to ˜pH 4. The aq. layer was then extracted withEtOAc (3×50 mL). The combined organics were then washed with ammoniumchloride (50 mL), water (50 mL), brine (50 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to provide99b.

Synthesis of (R)-methyl 2-amino-6,6,6-trifluorohexanoate (99c)

Compound 99b (230 mg, 0.81 mmol) was dissolved in DCM (10 mL) and MeOH(1 mL). A solution of 2M (Trimethylsilyl) Diazomethane, 2M solution inhexanes (0.6 mL, 1.2 mmol) was added dropwise. The reaction was allowedto stir for 20 minutes and then 2 drops of acetic acid were added. Thereaction mixture was concentrated under reduced pressure and. theresulting residue treated with DCM (5 mL) and TFA (5 mL). The mixturewas stirred for 90 minutes and then concentrated under reduced pressure.The residue was co-evaporated with DCM (20 mL×2) to provide 99c as itsTFA salt.

Synthesis of (R)-methyl2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6-trifluorohexanoate(99d)

99d was synthesized in a similar fashion to compound 63B, insteadreplacing 63A with (R)-methyl 2-amino-6,6,6-trifluorohexanoate TFA salt99c (100 mg, 0.75 mmol), to obtain 99d. MS (m/z) 494.2 [M+H]⁺;t_(R)=0.95 min.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6-trifluorohexan-1-ol(99e)

Compound 99d (100 mg, 0.2 mmol) was treated with THF (15 mL) and cooledto 0° C. under argon. To this solution was added 1M LiAlH₄ in THF (0.61mL, 0.61 mmol) and the reaction mixture stirred at 0° C. Uponcompletion, the reaction was diluted in EtOAc/H₂O and extracted withEtOAc (50 mL×3). The combined organics were then washed with aq.ammonium chloride (50 mL), water (50 mL), brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was subjected to silica gel chromatography eluting withhexanes-EtOAc to afford 99e. LCMS (m/z) 466.1 [M+H]⁺. t_(R)=1.14 min

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6-trifluorohexan-1-ol(99)

Compound 99e (75 mg, 0.16 mmol) was dissolved in TFA (5 mL) and allowedto stir for 1 h. The TFA was removed under reduced pressure and MeOH (10mL) was added. The mixture was stirred for 1 h and then filtered. Theeluent was removed in vacuo and the residue was treated with MeOH (10mL). The mixture was stirred for 16 h and then concentrated underreduced pressure. The residue was co-evaporated with MeOH (10 mL, x 3)and the resulting residue dried under high vacuum to afford compound 99as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.65 (dd, J=4.4, 1.4Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.77 (dd, J=8.5, 4.4 Hz, 1H),4.56 (ddt, J=10.9, 5.5, 3.1 Hz, 1H), 3.75 (d, J=5.3 Hz, 2H), 2.40-2.07(m, 2H), 1.94-1.76 (m, 2H), 1.66 (dddd, J=19.0, 16.1, 8.7, 5.9 Hz, 2H).¹⁹F NMR (376 MHz, Methanol-d₄) δ −68.49 (t, J=11.0 Hz), −77.91.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₃H₁₆F₃N₅O: 315.29; found:316.2; t_(R)=0.82 min.

Example 100

Synthesis of (E)-tert-butyl hept-2-enoate (100a)

To a solution of valeraldehyde (2.82 mL, 26.57 mmol) in THF (50 mL) wasadded (tert-butoxycarbonylmethylene)triphenylphosphorane (10 g, 26.57mmol) and the reaction mixture stirred for 16 h at rt. The solvents werethen removed under reduced pressure, and the residue slurried in diethylether and filtered. The filtrate was concentrated in vacuo and theresidue subjected to silica gel chromatography eluting withhexanes-EtOAc to give 100a. ¹H NMR (400 MHz, Methanol-d4) δ 6.85 (dt,J=15.5, 7.0 Hz, 1H), 5.73 (dt, J=15.6, 1.6 Hz, 1H), 2.26-2.11 (m, 2H),1.52-1.25 (m, 13H), 0.93 (t, J=7.2 Hz, 3H).

Synthesis of (R)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)heptanoate(100b)

2.5M Butyllithium (2.5M in Hexanes, 14.33 mL) was added to a stirredsolution of (R)-(+)-N-benzyl-alpha-methylbenzylamine (7.99 mL, 38.2mmol) in THF (100 mL) at −78° C. The reaction mixture was stirred for 30minutes, and then 100a (4.4 g, 23.88 mmol) in THF (50 mL) was addedslowly to the reaction mixture. The reaction mixture was then stirred at−78° C. for 2 h, quenched with sat. aq. NH₄Cl solution (100 mL) andallowed to warm to rt. EtOAc (200 mL) and water (100 mL) were added, andthe organic layer separated. The aqueous layer was extracted with EtOAc(3×50 mL) and the combined organics were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The resultingresidue was subjected to silica gel chromatography eluting withhexanes-EtOAc to provide 100b. ¹H NMR (400 MHz, Methanol-d4) δ 7.41 (d,J=7.2 Hz, 2H), 7.36-7.10 (m, 8H), 3.87-3.73 (m, 2H), 3.50 (d, J=15.0 Hz,1H), 3.24 (tt, J=9.4, 4.2 Hz, 1H), 2.04 (dd, J=14.4, 3.6 Hz, 1H), 1.89(dd, J=14.4, 9.4 Hz, 1H), 1.57-1.43 (m, 3H), 1.38 (s, 8H), 1.33-1.12 (m,7H), 0.87 (t, J=7.3 Hz, 3H).

Synthesis of (R)-3-(benzyl((S)-1-phenylethyl)amino)heptanoic acid (100c)

(R)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)heptanoate 100b (6.4 g,16.18 mmol) was dissolved in DCM (40 mL) and treated with TFA (20 mL).The reaction mixture was allowed to stir at 40° C. for 24 h and thenconcentrated under reduced pressure to provide 100c. LCMS (m/z) 340.0[M+H]⁺. t_(R)=0.94 min

Synthesis of (R)-3-(benzyl((S)-1-phenylethyl)amino)heptan-1-ol (100d)

(R)-3-(benzyl((S)-1-phenylethyl)amino)heptanoic acid 100c (5.5 g, 16.2mmol) was dissolved in THF (100 mL) under argon, and 1Mborane-tetrahydrofuran in THF (64.81 mL, 64.81 mmol) was slowly added.The reaction was allowed to stir for several h at rt. MeOH was slowlyadded to quench the reaction and the mixture was allowed to stir for anadditional 20 minutes. A ˜2N HCl (aq) (14 mL) solution was added and themixture concentrated under reduced pressure to afford a white solid. Thesolid material was suspended in DCM (100 mL) and filtered. The filtercake was rinsed with DCM (25 mL). The mother liquor was concentratedunder reduced pressure to afford a light yellow oil which was subjectedto silica gel chromatography eluting with DCM-MeOH to afford 100d. MS(m/z) 326.1 [M+H]⁺; t_(R)=0.82 min

Synthesis of (R)-3-aminoheptan-1-ol (100e)

(R)-3-(benzyl((S)-1-phenylethyl)amino)heptan-1-ol 100d (0.78 g, 2.4mmol) was treated with EtOH (25 mL) and 20% Pd(OH)₂/C (300 mg, 0.43mmol). The reaction vessel was purged 3x with H₂ gas and then allowed tostir for 2 days under H₂. The reaction mixture was filtered and solventswere removed under reduced pressure to afford 100e. ¹H NMR (400 MHz,Methanol-d4) δ 3.90-3.68 (m, 2H), 3.39-3.27 (m, 1H), 1.98-1.72 (m, 2H),1.72-1.57 (m, 3H), 1.39 (h, J=4.5, 4.0 Hz, 4H), 1.03-0.86 (m, 3H).

Synthesis of(R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol (100)

2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) was reacted with100e (65.6 mg, 0.5 mmol) followed by 2,4-dimethoxybenzylamine (150.21μl, 1 mmol) as described for the synthesis of 59B from 59A, to prepare100f. Compound 100f was then subjected to TFA (3 mL) for 1h as describedin the preparation of compound 59 from 59B to afford, 100 as its TFAsalt. MS (m/z) 276.1 [M+H]⁺; t_(R)=0.64 min; ¹H NMR (400 MHz,Methanol-d4) δ 8.63 (dd, J=4.4, 1.5 Hz, 1H), 7.82 (dd, J=8.5, 1.5 Hz,1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.64 (tt, J=7.9, 5.6 Hz, 1H),3.72-3.59 (m, 2H), 1.99-1.83 (m, 2H), 1.81-1.66 (m, 2H), 1.46-1.29 (m,4H), 0.97-0.82 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.56.

Example 101

Synthesis of(R)-N-(2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(101)

Compound 101 was prepared following the procedure described in Example84, using 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (30 mg, 0.14mmol) and reacting sequentially with(R)-N-(2-amino-2-methylhexyl)acetamide hydrochloride 61E (28.72 mg, 0.14mmol) followed by 2,4-dimethoxybenzylamine (82.69 μl, 0.55 mmol). Theresulting product was then subjected to TFA treatment as described inthe preparation of 84 from 84G, to provide 101 as its TFA salt. MS (m/z)335.2 [M+H]⁺; t_(R)=0.64 min; ¹H NMR (400 MHz, Methanol-d4) δ 8.54 (t,J=2.9 Hz, 2H), 7.62 (dd, J=8.8, 2.5 Hz, 1H), 3.99-3.86 (m, 1H), 3.51 (d,J=14.0 Hz, 1H), 2.26-2.05 (m, 1H), 1.95 (s, 4H), 1.54 (s, 3H), 1.45-1.27(m, 4H), 0.99-0.80 (m, 3H); ¹⁹F NMR (376 MHz, Methanol-d4) δ −78.04,−118.27 (d, J=8.8 Hz).

Example 102

Synthesis of(3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol(102)

A solution of compound 43B (131.5 mg, 0.730 mmol), compound 88d (212.2mg, 1.415 mmol), and BOP (392.7 mg, 0.888 mmol) in DMF (7 mL) wasstirred at rt as DBU (0.33 mL, 2.209 mmol) was added. The reactionmixture was stirred at rt for 17.5 h, diluted with water (7 mL), andthen the mixture was filtered. The filtrate was subjected to preparativeHPLC (Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq.acetonitrile with 0.1% TFA, over 20 min. gradient) and the productfractions were combined, concentrated under reduced pressure to obtainthe crude product. The crude product was re-subjected to preparativeHPLC (Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq.acetonitrile with 0.1% TFA, over 20 min. gradient), and the combinedproduct fractions concentrated under reduced pressure, co-evaporatedwith methanol (10 mL×4), and dried to obtain compound 102 as its TFAsalt. ¹H NMR (400 MHz, Methanol-d4) δ 8.67 (d, J=9.6 Hz, 0H), 8.55 (d,J=2.4 Hz, 1H), 7.65 (dd, J=8.8, 2.5 Hz, 1H), 4.63-4.54 (m, 1H),4.51-4.39 (m, 1H), 4.39-4.26 (m, 1H), 4.03 (dddd, J=16.5, 6.0, 4.9, 3.2Hz, 1H), 1.87-1.73 (m, 2H), 1.49-1.28 (m, 4H), 0.98-0.83 (m, 3H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −77.71, −117.85 (d, J=8.3 Hz), −231.37 (td,J=47.3, 16.5 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂OF₂N₅O:312.16; found: 312.16; t_(R)=0.70 min.

Example 103

Synthesis of (R)-benzyl (1-hydroxyhexan-2-yl)carbamate (103a)

A solution of (R)-2-aminohexan-1-ol (1.853 g, 15.81 mmol) and sodiumbicarbonate (1961.6 mg, 31.63 mmol) in water (80 mL) was stirred at rtand benzyl chloroformate (2.7 mL, 95% purity, 18.98 mmol) was added.After stirring for 1 h at rt, the mixture was extracted with EtOAc (100mL x 1, 80 mL x 2). The combined extracts were washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting with 0-100% EtOAc in hexanes toobtain 103a. ¹H NMR (400 MHz, Methanol-d4) δ 7.44-7.18 (m, 5H), 6.75 (d,J=8.7 Hz, 0H), 5.07 (d, J=2.2 Hz, 2H), 3.57 (dt, J=11.1, 5.4 Hz, 1H),3.48 (d, J=5.6 Hz, 2H), 1.58 (dq, J=14.0, 8.4, 6.4 Hz, 1H), 1.35 (dq,J=14.3, 7.4, 6.4 Hz, 5H), 0.91 (t, J=5.6 Hz, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₁₄H₂₂NO₃: 252.16; found: 251.80; t_(R)=0.90 min.

Synthesis of benzyl (1-oxohexan-2-yl)carbamate (103b)

To a stirred solution of oxalyl chloride (0.125 mL, 1.432 mmol) in DCM(10 mL) cooled with an −78° C. bath was added DMSO (0.203 mL, 2.865mmol) in DCM (2 mL) over 8 min. After 15 min, a solution of compound103a (300 mg, 1.194 mmol) in DCM (4 mL) was added to the reactionmixture. The mixture was stirred at −78° C. for 30 min. and thentriethylamine (0.832 mL, 5.968 mmol) was added with vigorous stirring.The resulting mixture was allowed to warm to rt, diluted with DCM (20mL), washed with water (30 mL×3), brine (20 mL), dried (MgSO₄), filteredand concentrated under reduced pressure. The residue was subjected tosilica gel chromatography eluting with 0-50% EtOAc in hexanes to obtain103b. ¹H NMR (400 MHz, Methanol-d4) δ 9.41 (d, J=80.7 Hz, 0H), 7.51-7.06(m, 5H), 5.08 (d, J=2.1 Hz, 2H), 4.43 (d, J=3.9 Hz, 1H), 3.57 (dd,J=9.8, 5.1 Hz, 1H), 1.65 (dd, J=11.3, 6.7 Hz, 1H), 1.46-1.20 (m, 5H),0.90 (t, J=6.3 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₁₄H₂₀NO₃: 250.14; found: 249.83; t_(R)=0.93 min.

Synthesis of benzyl (2-hydroxyheptan-3-yl)carbamate (103c)

To a solution of compound 103b (277.0 mg, 1.111 mmol) dissolved indiethyl ether (10 mL) and cooled to −78° C. was added dropwise 1.57 Mmethyllithium in diethyl ether (1.557 mL, 2.444 mmol). After 10 min,saturated ammonium chloride (10 mL) was added to the reaction mixtureand the resulting mixture was allowed to warm to rt for 45 min. Themixture was extracted with EtOAc (50 mL×3), the combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with 0-70% EtOAc in hexanes to obtain compound103c as a mixture of 4 diastereomers. ¹H NMR (400 MHz, Methanol-d4) δ7.44-7.19 (m, 5H), 5.08 (d, J=3.0 Hz, 2H), 3.83-3.57 (m, 1H), 3.54-3.40(m, 1H), 1.76-1.41 (m, 2H), 1.43-1.24 (m, 6H), 1.12 (dd, J=9.4, 6.4 Hz,3H), 0.90 (dd, J=7.9, 4.9 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₅H₂₄NO₃: 266.18; found: 265.81; t_(R)=0.93 min.

Synthesis of 3-aminoheptan-2-ol (103d)

Compound 103c (59.6 mg, 0.225 mmol) and 20% Pd(OH)₂ on carbon (15.2 mg)were dissolved in EtOH (2 mL) and stirred under H₂ atmosphere. After 2h, the reaction mixture was filtered through Celite pad and the removedsolid was washed with EtOH (10 mL). The filtrate and washing wereconcentrated under reduced pressure and the crude compound, 103d, wasused without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₇H₁₈NO: 132.14; found: 131.91; t_(R)=0.37 min.

Synthesis3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(103e)

To a solution of compound 103d (29.5 mg, 0.225 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (37.4 mg, 0.187 mmol) in dioxane (2mL) was added N,N-diisopropylethylamine (0.05 mL, 0.281 mmol). After 20min, additional N,N-diisopropylethylamine (0.080 mL, 0.449 mmol) and2,4-dimethoxybenzylamine (0.10 mL, 0.674 mmol) were added and theresulting mixture was heated at 115° C. bath for 7 h. The reactionmixture was allowed to cool to rt, diluted with water (50 mL), extractedwith DCM (25 mL×2). The combined organic extracts were washed with water(25 mL×2), dried over MgSO₄, filtered and then concentrated in vacuo.The residue was subjected to silica gel chromatography eluting with0-100% EtOAc in hexanes to obtain compound 103e. ¹H NMR (400 MHz,Methanol-d4) δ 8.31 (dt, J=4.3, 1.0 Hz, 0.85H), 8.05 (s, 0.15H), 7.63(s, 1H), 7.48 (dd, J=8.5, 4.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H),6.52 (d, J=2.3 Hz, 1H), 6.48-6.38 (m, 1H), 4.64-4.47 (m, 2H), 4.35-4.21(m, 1H), 4.00-3.87 (m, 1H), 3.83 (two s, 3H), 3.76 (two s, 3H), 3.35 (s,1H), 1.90-1.52 (m, 2H), 1.33 (m, 4H), 1.16 (m, 3H), 0.97-0.78 (m, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₃₄N₅O₃: 426.25; found:426.17; t_(R)=1.00 min.

Synthesis of 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(103)

Compound 103e (17.4 mg, 40.9 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was concentrated underreduced pressure and co-evaporated with MeOH (10 mL). The resultingresidue was dissolved in MeOH (1 mL) and concentrated ammonium hydroxide(0.1 mL). The mixture was stirred for 10 min. at rt and thenconcentrated under reduced pressure to dryness. The residue wasdissolved in DMF-water (1:1, 5 mL) and filtered through aCelite/membrane filter. The filtrate was subjected to preparative HPLC(Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient). The product fractions werecombined, concentrated under reduced pressure, co-evaporated withmethanol (10 mL×3), and dried under high vacuum to obtain compound 103as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dt, J=4.4, 1.2Hz, 1H), 7.84 (dt, J=8.5, 1.4 Hz, 1H), 7.77 (ddd, J=8.5, 4.4, 1.5 Hz,1H), 4.47-4.31 (m, 1H), 3.99 (tq, J=6.5, 3.5 Hz, 0.5H), 3.94 (dd, J=6.6,5.5 Hz, 0.5H), 1.95-1.82 (m, 0.5H), 1.82-1.72 (m, 1H), 1.72-1.63 (m,0.5H), 1.48-1.25 (m, 4H), 1.22 (d, J=6.4 Hz, 1.5H), 1.19 (d, J=6.4 Hz,1.5H), 0.89 (two d, J=6.9, Hz each, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₄H₂₂N₅O: 276.18; found: 276.15; t_(R)=0.68 min.

Example 104

Synthesis of (S)-benzyl (1-hydroxyhexan-2-yl)carbamate (104a)

To a mixture of (S)-2-aminohexan-1-ol (504.4 mg, 4.30 mmol) and sodiumbicarbonate (533.9 mg, 8.61 mmol) in water (20 mL) was added benzylchloroformate (0.74 mL, 95% purity, 5.17 mmol). The resulting mixturewas vigorously stirred at rt overnight. The solid was dissolved withEtOAc (75 mL) and the mixture extracted with EtOAc (75 mL×2). Theorganic extracts were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo to obtain white solids. The solids were subjectedto silica gel chromatography eluting with 0-100% EtOAc in hexanes toobtain compound 104a. ¹H NMR (400 MHz, Methanol-d₄) δ 7.42-7.22 (m, 5H),5.07 (d, J=2.1 Hz, 2H), 3.59 (d, J=8.0 Hz, 1H), 3.48 (d, J=5.6 Hz, 2H),1.59 (d, J=10.8 Hz, 1H), 1.34 (td, J=15.4, 11.8, 7.3 Hz, 6H), 0.91 (t,J=6.0 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₂NO₃: 252.16;found: 251.78; t_(R)=0.88 min.

Synthesis of benzyl (1-oxohexan-2-yl)carbamate (104b)

To a stirred solution of oxalyl chloride (0.052 mL, 0.602 mmol) in DCM(1.5 mL) at −78° C. was added DMSO (0.086 mL, 1.205 mmol) in DCM (2 mL)over 8 min. After 15 min, a solution of compound 104a (108.1 mg, 0.430mmol) in DCM (1.5 mL) was added to the reaction mixture. The mixture wasstirred at −78° C. for 30 min. and then triethylamine (0.174 mL, 1.248mmol) was added with vigorous stirring. The resulting mixture wasallowed to warm to rt over 45 min. The mixture was diluted with DCM (30mL), washed with water (30 mL×3), brine (25 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to obtain the mixture104b. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₀NO₃: 250.14; found:249.79; t_(R)=0.91 min.

Synthesis of benzyl (2-hydroxyheptan-3-yl)carbamate (104c)

To a solution of compound 104b (107.3 mg, 0.430 mmol), dissolved indiethyl ether (4 mL) and cooled to −78° C. was added 1.57 Mmethyllithium in diethyl ether (0.685 mL, 1.076 mmol) dropwise. After 10min, saturated aq. ammonium chloride (7 mL) was added to the reactionmixture and the resulting mixture was allowed to warm to rt for 45 min.The mixture was extracted with EtOAc (25 mL×2), and the combined organicextracts washed with brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was subjected to silica gel chromatography elutingwith 0-70% EtOAc in hexanes to obtain compound 104c as a mixture of 4diastereomers. ¹H NMR (400 MHz, Methanol-d₄) δ 7.42-7.20 (m, 5H), 6.63(dd, J=102.5, 9.6 Hz, 1H), 5.08 (d, J=3.3 Hz, 2H), 3.80-3.54 (m, 1H),3.52-3.41 (m, 1H), 1.75-1.42 (m, 2H), 1.42-1.27 (m, 5H), 1.12 (dd,J=9.3, 6.4 Hz, 3H), 0.90 (d, J=3.5 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₅H₂₄NO₃: 266.18; found: 265.81; t_(R)=1.06 min.

Synthesis of 3-aminoheptan-2-ol (104d)

Compound 104c (71.68 mg, 0.270 mmol) and 20% Pd(OH)₂ on carbon (19 mg)were dissolved in EtOH (2 mL) and stirred under H₂ atmosphere. After 2h, the reaction mixture was filtered through Celite pad and the removedsolid washed with EtOH (5 mL). The filtrate and washings wereconcentrated under reduced pressure to provide 104d that was usedwithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₇H8NO: 132.14; found: 131.91; t_(R)=0.51 min.

Synthesis of3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(104e)

To a solution of compound 104d (35.45 mg, 0.270 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (5.02 mg, 0.225 mmol) in dioxane (3mL) was added N,N-diisopropylethylamine (0.06 mL, 0.338 mmol). After 20min. additional N,N-diisopropylethylamine (0.096 mL, 0.540 mmol) and2,4-dimethoxybenzylamine (0.120 mL, 0.811 mmol) were added and theresulting mixture was heated at 115° C. bath for 6 h. The reactionmixture was cooled to rt, diluted with water (30 mL), and extracted withDCM (20 mL×2). The organic extracts were combined, washed with water (30mL×2), brine (25 mL), dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was subjected to silica gel chromatographyeluting with 0-100% EtOAc in hexanes to obtain compound 104e. ¹H NMR(400 MHz, Methanol-d4) δ 8.31 (ddd, J=4.2, 1.5, 0.8 Hz, 1H), 7.63 (d,J=8.4 Hz, 1H), 7.48 (dd, J=8.5, 4.2 Hz, 1H), 7.25-7.08 (m, 1H),6.60-6.37 (m, 2H), 4.84 (s, 3H), 4.54 (d, J=5.3 Hz, 2H), 4.35-4.22 (m,1H), 3.83 (d, J=10.3 Hz, 3H), 3.79-3.73 (m, 3H), 1.88-1.52 (m, 2H),1.46-1.28 (m, 4H), 1.23-1.12 (m, 3H), 0.86 (td, J=7.0, 2.2 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₃₄N₅O₃: 426.25; found:426.19; t_(R)=0.97 min.

Synthesis of 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol(104)

Compound 104e (27.3 mg, 64.2 umol) was dissolved in TFA (1 mL) andstirred at rt for 1 h. The reaction mixture was concentrated underreduced pressure and co-evaporated with MeOH (10 mL). The resultingresidue was dissolved in MeOH (1 mL) and concentrated ammonium hydroxide(0.1 mL). The reaction mixture was stirred at rt, and then concentratedunder reduced pressure to dryness. The residue was treated withDMF-water (1:1, 5 mL). The insoluble material was removed via filtrationthrough a Celite/membrane filter, and the filtrate was subjected topreparative HPLC (Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile-70%aq. acetonitrile with 0.1% TFA, over 20 min. gradient). The fractionswere combined, concentrated under reduced pressure, co-evaporated withmethanol (10 mL×3), and dried in vacuum overnight to obtain 104 as itsTFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dt, J=4.4, 1.2 Hz, 1H),7.84 (dt, J=8.5, 1.4 Hz, 1H), 7.77 (ddd, J=8.5, 4.4, 1.5 Hz, 1H),4.46-4.40 (m, 0.5H), 4.37 (m, 1H), 4.00 (m, 0.5H), 3.97-3.88 (m, 0.5H),1.88 (m, 0.5H), 1.82-1.72 (m, 1H), 1.72-1.62 (m, 0.5H), 1.48-1.25 (m,4H), 1.22 (d, J=6.4 Hz, 1.5H), 1.19 (d, J=6.4 Hz, 1.5H), 0.89 (two t,J=6.8 Hz each, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₄H₂₂N₅O:276.18; found: 276.15; t_(R)=0.68 min.

Example 105

Synthesis of 2,4,7-trichloropyrido[3,2-d]pyrimidine (105a)

A mixture of pyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione 19A (supplied byAstatech, Inc., 2.00 g, 12.26 mmol), phosphorus pentachloride (15.32 g,73.56 mmol) and phosphorus oxychloride (22.86 mL, 245.20 mmol) in asealed, thick-walled reaction tube, was stirred at 160° C. for 5 h. Themixture was concentrated in vacuo and the residue was dissolved in DCM(100 mL). The organic solution was washed with water (100 mL), brine(100 mL), dried over MgSO₄, filtered and then concentrated in vacuo. Theresidue was subjected to silica gel chromatography eluting with 0-50%EtOAc in hexanes to obtain compound 105a. ¹H NMR (400 MHz, Chloroform-d)δ 9.02 (d, J=2.2 Hz, 21H), 8.29 (d, J=2.2 Hz, 21H). LCMS-ESI⁺ (m/z):t_(R)=0.86 min.

Synthesis of(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(105b)

To a solution of compound 105a (336 mg, 1.066 mmol) and(R)-2-aminohexan-1-ol 86a (137.5 mg, 1.173 mmol) in dioxane (4 mL) wasadded N,N-diisopropylethylamine (0.23 mL, 1.292 mmol). The mixture wasstirred for 40 min. and then additional N,N-diisopropylethylamine (0.38mL, 2.132 mmol) and 2,4-dimethoxybenzylamine (0.473 mL, 3.198 mmol) wereadded. The resulting mixture was heated at 115° C. for 2 h. The reactionmixture was cooled to rt, diluted with water (30 mL) and extracted withDCM (30 mL). The organic extracts were washed with water (30 mL), brine(30 mL), dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was subjected to silica gel chromatography eluting with 0-100%EtOAc in hexanes to obtain compound 105b. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₂₂H₂₉ClN₅O₃: 446.20; found: 446.23, t_(R)=0.80 min.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(105c)

To a solution of compound 105b (50 mg, 0.113 mmol) in dioxane (2 mL) wasadded sodium methoxide (25 wt. %, 0.064 mL, 0.280 mmol) in a microwavevial. The resulting mixture was heated at 120° C. for 45 min. in amicrowave reactor. The reaction mixture was concentrated in vacuo andthe residue was dissolved in methanol (2 mL) and sodium methoxide (25wt. %, 0.2 mL, 0.874 mmol). The resulting mixture was heated at 150° C.for 1 h in a microwave reactor. The reaction mixture was diluted withwater (25 mL) and extracted with EtOAc (25 mL×2). The combined extractswere washed with saturated aqueous ammonium chloride (25 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to obtain crudecompound 105c. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₃₂N₅O₄:442.25; found: 442.23; t_(R)=0.82 min.

Synthesis of(R)-2-((2-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(105)

The compound 105c was dissolved in TFA (1 mL) and stirred at rt for 1 h.The reaction mixture was concentrated under reduced pressure andco-evaporated with MeOH (10 mL). The resulting residue was subjected topreparative HPLC (Gemini 10u C18 110A, AXIA; 5% aq. acetonitrile-50% aq.acetonitrile with 0.1% TFA, over 20 min. gradient). The productfractions were concentrated in vacuo, co-evaporated with methanol (10mL×3), and dried under vacuum to obtain compound 105 as its TFA salt. ¹HNMR (400 MHz, Methanol-d₄) δ 8.32 (d, J=2.5 Hz, 1H), 7.22 (d, J=2.6 Hz,1H), 4.58-4.39 (m, 1H), 4.00 (s, 4H), 3.77-3.60 (m, 3H), 1.72 (dtd,J=14.7, 8.5, 8.0, 5.4 Hz, 2H), 1.51-1.22 (m, 5H), 1.00-0.80 (m, 4H). ¹⁹FNMR (376 MHz, Methanol-d₄) δ −77.51. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₄H₂₂N₅O₂: 292.18; found: 292.19; t_(R)=0.45 min.

Example 106

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-ethoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(106a)

To a solution of compound 105c (40 mg, 0.090 mmol) in EtOH (3 mL) wasadded sodium ethoxide (21 wt. %, 0.335 mL, 0.897 mmol) in a microwavevial. The resulting mixture was heated at 120° C. for 45 min. in amicrowave reactor. The reaction mixture was concentrated in vacuo andthe residue was then dissolved in water (25 mL) and EtOAc (25 mL). Theorganic layer was separated and washed with saturated aqueous ammoniumchloride, dried over MgSO₄, filtered and then concentrated in vacuo toobtain crude compound 106a. LCMS-ESI⁺ (m/z): [M+H]₊ calculated forC₂₄H₃₄N₅O₄: 456.26; found: 456.23; t_(R)=0.76 min.

Synthesis of(R)-2-((2-amino-7-ethoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(106)

The compound 106a was dissolved in TFA (1 mL) and stirred at rt for 1 h.The reaction mixture was concentrated in vacuo and co-evaporated withMeOH (10 mL). The resulting residue was dissolved in MeOH (1 mL) andconcentrated ammonium hydroxide (0.1 mL). The mixture was stirred at 50°C. for 10 min. and then concentrated under reduced pressure. Theresulting residue was subjected to preparative HPLC (Gemini 10u C18110A, AXIA; 5% aq. acetonitrile-50% aq. acetonitrile with 0.1% TFA, over20 min. gradient). The product fractions were concentrated in vacuo,co-evaporated with methanol (10 mL×3), and then dried under high vacuumto obtain compound 106 as its TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ7.94 (d, J=2.6 Hz, 1H), 6.83 (d, J=2.6 Hz, 1H), 4.02 (q, J=7.0 Hz, 3H),3.55 (d, J=4.9 Hz, 3H), 1.33 (t, J=7.0 Hz, 4H), 1.30-1.15 (m, 4H),0.91-0.63 (m, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.50. LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₅H₂₄N₅O₂: 306.19; found: 306.20;t_(R)=0.51 min.

Example 107

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(107a)

A mixture of compound 105c (35 mg, 0.078 mmol), methylboronic acid (18.8mg, 0.314 mmol), potassium phosphate tribasic (50.0 mg, 0.235 mmol), andpalladium tetrakis(triphenylphosphine (18.14 mg, 0.016 mmol) in water (2mL) and dioxane (2 mL) was stirred at 150° C. for 45 min. in a microwavereactor. The reaction mixture was diluted with water (25 mL) andextracted with EtOAc (25 mL). The organic layer was washed with water(25 mL), brine (25 mL), dried over MgSO₄, filtered and then concentratedunder reduced pressure to obtain crude compound 107a. LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₂₃H₃₂N₅O₃: 292.18; found: 426.22; t_(R)=0.70 min.

Synthesis of(R)-2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol(107)

The compound 107a was dissolved in TFA (1 mL) and stirred at rt for 1 h.The reaction mixture was concentrated in vacuo and the residueco-evaporated with MeOH (10 mL). The resulting residue was dissolved inMeOH (1 mL) and concentrated ammonium hydroxide (0.1 mL). The mixturewas stirred for 10 min. at 50° C. and then concentrated under reducedpressure. The resulting residue was subjected to preparative HPLC(Gemini 10u C18 110A, AXIA; 5% aq. acetonitrile-50% aq. acetonitrilewith 0.1% TFA, over 20 min. gradient). The product fractions wereconcentrated in vacuo, co-evaporated with methanol (10 mL×3), and driedunder high-vacuum to obtain compound 107 as its TFA salt. ¹H NMR (400MHz, Methanol-d4) δ 8.53-8.46 (m, 1H), 7.62 (tt, J=1.9, 1.0 Hz, 1H),4.51 (dtd, J=9.0, 5.5, 3.1 Hz, 1H), 3.72 (d, J=5.3 Hz, 2H), 2.51 (d,J=2.2 Hz, 3H), 1.83-1.62 (m, 2H), 1.49-1.29 (m, 4H), 0.98-0.86 (m, 3H).¹⁹F NMR (376 MHz, Methanol-d4) δ −77.52. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₄H₂₂N₅O: 276.18; found: 276.16; t_(R)=0.50 min.

Example 108

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pent-4-en-1-ol(108b)

To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (50 mg, 0.250 mmol)and (R)-2-aminopent-4-en-1-ol hydrochloride 108a (26.6 mg, 0.280 mmol,Chiralix B.V., Netherland) in dioxane (2 mL) was addedN,N-diisopropylethylamine (0.09 mL, 0.500 mmol). The mixture was stirredovernight and then additional N,N-diisopropylethylamine (0.09 mL, 0.500mmol) and 2,4-dimethoxybenzylamine (0.403 mL, 2.727 mmol) were added.The resulting mixture was heated at 120° C. overnight. The reactionmixture was allowed to cool to rt, diluted with water (25 mL) andextracted with EtOAc (25 mL×3). The organic extracts were washed withwater (25 mL), brine (25 mL), dried over MgSO), filtered and thenconcentrated in vacuo to obtain the crude compound 108b. LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₂₁H₂₆N₅O₃: 396.20; found: 396.14,t_(R)=0.69 min.

Synthesis of(R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pent-4-en-1-ol (108)

The compound 108b (99 mg) was dissolved in TFA (3 mL) and stirred at rtfor 3 h. The reaction mixture was concentrated under reduced pressureand co-evaporated with MeOH (10 mL). The resulting residue was subjectedto preparative HPLC (Gemini 10u C18 110A, AXIA; 5% aq. acetonitrile-50%aq. acetonitrile with 0.1% TFA, over 20 min. gradient). The productfractions were concentrated in vacuo, co-evaporated with methanol (10mL×3), and dried under high vacuum to obtain compound 108 as its TFAsalt. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (dd, J=4.3, 1.5 Hz, 1H),7.89-7.65 (m, 2H), 6.02-5.70 (m, 1H), 5.24-5.10 (m, 1H), 5.11-4.99 (m,1H), 4.63-4.45 (m, 1H), 3.76 (d, J=5.3 Hz, 2H), 2.68-2.35 (m, 2H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −77.49. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₂H₁₆N₅O: 246.14; found: 246.09, t_(R)=0.45 min.

Example 110

Synthesis of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol(110)

To 77A (40 mg, 0.09 mmol) was added TFA (3 mL) and the mixture stirredfor 2 h. The reaction mixture was concentrated under reduced pressureand the residue subjected to preparative HPLC (Synergi 4u Polar-RP 80A,Axia; 10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20min. gradient) to afford 110 as its TFA salt. LCMS (m/z): 292.12 [M+H]⁺;t_(R)=0.50 min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d4) δ 8.63(dd, J=4.4, 1.4 Hz, 1H), 7.87 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (dd, J=8.5,4.4 Hz, 1H), 4.61-4.34 (m, 1H), 3.76 (d, J=5.3 Hz, 2H), 1.96-1.70 (m,2H), 1.64-1.51 (m, 2H), 1.19 (s, 6H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ−77.52.

Example 111

Synthesis of (3R,5R)-3-methyl-3-pentyl-5-phenylmorpholin-2-one (111A)

To a solution of 94c (2 g, 10.57 mmol) in THF (50 ml) at −78° C. wasadded 2M boron trifluoride diethyl etherate in THF (2.76 ml, 22.39 mmol,2.1 equiv.) over 10 minutes. After 90 minutes, 2M pentylmagnesiumchloride solution in THF (11.19 ml, 22.38 mmol, 2.1 equiv.) was addedslowly. The reaction was stirred for 2 h and then quenched with sat.NH₄Cl (200 mL). The mixture was allowed to warm to rt and then dilutedwith water (200 mL). The mixture was extracted with EtOAc (3×300 mL) andthe combined extracts washed with water (3×500 mL), brine (300 mL),dried over NaSO₄, and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography eluting with hexanes-EtOAc toafford 111A. LCMS (m/z): 262.06 [M+H]⁺; t_(R)=1.14 min. on LC/MS MethodA.

Synthesis of(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylheptan-1-ol (111B)

To a solution of 111A (1.65 g, 6.31 mmol) in THF (100 ml) at 0° C. wasadded 2M lithium borohydride in THF (6.35 ml, 12.7 mmol, 2 equiv.). Thereaction was warmed to rt and stirred overnight. The mixture was thenquenched with water (100 mL) and extracted with EtOAc (3×300 mL). Thecombined organics were washed with water (500 mL), brine (100 mL), driedover Na₂SO₄, and concentrated under reduced pressure to afford 111B thatwas used without further purification. LCMS (m/z): 266.05 [M+H]⁺;t_(R)=0.64 min. on LC/MS Method A.

Synthesis of (R)-2-amino-2-methylheptan-1-ol (111C)

To a solution of 111B (1.66 g, 6.25 mmol) in EtOH (20 mL) was addedPd(OH)₂/C (20% wt %, 0.92 g) and 4M HCl in dioxane (2.37 ml, 9.50 mmol,1.5 equiv.). The mixture was stirred under and atmosphere of H₂ at 70°C. overnight. The reaction was then filtered through Celite andconcentrated to afford 111C that was used without further purification.LCMS (m/z): 145.95 [M+H]⁺; t_(R)=0.57 min. on LC/MS Method A.

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol(111D)

To 2,4-dichloropyrido[3,2-d]pyrimidine (118.89 mg, 0.59 mmol) in dioxane(12 mL) was added 111C (135 mg, 0.74 mmol, 1.25 equiv.), andN,N-diisopropylethylamine (0.78 ml, 4.46 mmol, 7.5 equiv.). The reactionmixture was stirred at 80° C. overnight. 2,4-dimethoxybenzylamine (0.27ml, 1.85 mmol, 3.1 equiv.) was added and the mixture was heated to 100°C. for 6 h. The reaction mixture was allowed to cool, diluted with EtOAc(50 mL), washed with water (50 mL), saturated NH₄Cl (50 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography eluting with hexanes-EtOAc toafford 111D. LCMS (m/z): 440.30 [M+H]⁺; t_(R)=0.93 min. on LC/MS MethodA.

Synthesis of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol(111)

To 111D (155 mg, 0.35 mmol) was added TFA (3 mL). After 1 h, thereaction was concentrated under reduced pressure and the residuesubjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 111 as its TFA salt. LCMS (m/z): 290.15 [M+H]⁺; t_(R)=0.72min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d4) δ 8.63 (dd, J=4.3,1.5 Hz, 1H), 7.86-7.80 (m, 1H), 7.77 (dd, J=8.5, 4.3 Hz, 1H), 3.98 (d,J=11.2 Hz, 1H), 3.72 (d, J=11.2 Hz, 1H), 2.16-2.04 (m, 1H), 1.92 (tt,J=11.1, 4.9 Hz, 1H), 1.55 (s, 3H), 1.42-1.28 (m, 7H), 0.93-0.85 (m, 3H).¹⁹F NMR (377 MHz, Methanol-d4) δ −77.58.

Example 112

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol(112A)

To a solution of 84E (119.98 mg, 0.55 mmol) in dioxane (10 mL) was added111C (125 mg, 0.69 mmol, 1.25 equiv.) and N,N-diisopropylethylamine(0.72 ml, 4.13 mmol, 6 equiv.). The mixture was stirred at 80° C.overnight. 2,4-dimethoxybenzylamine (0.2 ml, 1.38 mol, 2.5 equiv.) wasadded and the reaction heated to 100° C. for 6 h. The reaction mixturewas allowed to cool, diluted with EtOAc (50 mL), washed with water (50mL), sat. NH₄Cl (50 mL), dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was subjected to silica gelchromatography eluting with hexanes-EtOAc to afford 112A. LCMS (m/z):458.26 [M+H]⁺; t_(R)=1.00 min. on LC/MS Method A.

Synthesis of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol(112)

To 112A (105 mg, 0.23 mmol) was added TFA (3 mL). After 1 h, thereaction mixture was concentrated under reduced pressure and subjectedto preparative HPLC (Synergi 4u Polar-RP 80A, Axia; 10% aq.acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 112 as its TFA salt. LCMS (m/z): 308.14 [M+H]⁺; t_(R)=0.75min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.54 (d, J=2.5Hz, 1H), 8.22 (s, 1H), 7.62 (ddd, J=8.7, 2.4, 0.8 Hz, 1H), 3.96 (d,J=11.2 Hz, 1H), 3.70 (d, J=11.2 Hz, 1H), 2.13-2.02 (m, 1H), 1.91 (s,1H), 1.53 (s, 3H), 1.41-1.28 (m, 7H), 0.93-0.84 (m, 3H). ¹⁹F NMR (377MHz, Methanol-d4) δ −77.56, −118.19 (dd, J=8.7, 4.2 Hz).

Example 113

Synthesis of N-(7-fluoro-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide(113a)

Acetic anhydride was cooled to 0° C. under nitrogen and2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol 43B (200 mg, 1.11 mmol;Supplied by Medicilon, Shanghai) was added. The reaction mixture wasthen heated to 110° C. for 4 h. The mixture was cooled and concentratedunder reduced pressure. The residue was triturated with DCM (20 mL), andthe solids removed by filtration and air dried to provide of compound113a as a solid. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₉H₇FN₄O₂:223.06; found: 222.96; t=0.58 min.

Synthesis ofN⁴-(tert-butyl)-7-methoxypyrido[3,2-d]pyrimidine-2,4-diamine (113)

113a was suspended in POCl₃ (5 mL) and heated to 110° C. for 1 h. Thereaction was then cooled and POCl₃ removed under reduced pressure. Theresidue was co-evaporated with toluene (15 mL) and then treated withinTHF (5 mL). tert-Butylamine (70 μL, 0.66 mmol) was added and the mixturestirred at rt for 15 minutes. 25% Sodium methoxide in methanol (100 μL,0.45 mmol) was added and the reaction mixture heated in a sealed vesselat 80° C. The reaction mixture was allowed to cool to rt and wasdirectly subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia;10% aq. acetonitrile-70% aq. acetonitrile with 0.1% TFA, over 20 min.gradient). The product fractions were concentrated in vacuo to afford113 as its TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J=2.5 Hz,1H), 8.04 (s, 1H), 7.18 (d, J=2.6 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 9H).¹⁹F NMR (376 MHz, Methanol-d4) δ −77.51. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₂H₁₇N₅O: 248.14; found: 248.09; t_(R)=0.81 min.

Example 114

Synthesis of(R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(114A)

To a solution of 94G (75 mg, 0.30 mmol) and 19B (51 mg, 0.30 mmol) inTHF (5 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.90 mmol).After stirring at 80° C. for 23 h, the reaction was cooled to ambienttemperature, diluted with EtOAc (50 mL), washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc (0-75%) to provide 114A. LCMS (m/z): 329.11 [M+H]⁺;t_(R)=1.27 min. on LC/MS Method A.

Synthesis of(R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(114B)

To a solution of 114A in THF (5 mL) was added N,N-diisopropylethylamine(0.16 mL, 0.90 mmol) followed by 2,4-dimethoxybenzylamine (0.25 mL, 1.5mmol). After stirring at 100° C. for 18 h, the reaction was cooled toambient temperature, diluted with EtOAc (100 mL), washed with water (100mL) and brine (100 mL), dried over Na₂SO₄, then filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with hexanes-EtOAc (15-100%) to provide 114B.LCMS (m/z): 460.29 [M+H]⁺; t_(R)=0.94 min. on LC/MS Method A.

Synthesis of(R)-2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(114)

To 114B (11 mg, 0.02 mmol) was added TFA (3 mL). After 4 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH (20 mL) and filtered. After stirringovernight, the solution was concentrated in vacuo to afford 114 as a TFAsalt. LCMS (m/z): 310.12 [M+H]⁺; t_(R)=0.98 min. on LC/MS Method A. ¹HNMR (400 MHz, Methanol-d₄) δ 8.59 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 7.91(d, J=2.1 Hz, 1H), 3.97 (d, J=11.3 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H),2.10 (ddd, J=13.9, 10.9, 5.0 Hz, 1H), 1.96-1.82 (m, 1H), 1.54 (s, 3H),1.35 (qt, J=6.8, 2.8 Hz, 4H), 0.95-0.88 (m, 3H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.61.

Example 115

Synthesis of(R)-2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(115A)

To a solution of 94G (55 mg, 0.30 mmol) and 84E (65 mg, 0.30 mmol) inTHF (5 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.90 mmol).After stirring at 80° C. for 18 h, the reaction was cooled to ambienttemperature, diluted with EtOAc (50 mL), washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 115A. LCMS (m/z): 313.08 [M+H]⁺;t_(R)=1.19 min. on LC/MS Method A.

Synthesis of(R)-2-((2,7-bis((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(115B)

To a solution of 115A in THF (5 mL) was added N,N-diisopropylethylamine(0.16 mL, 0.90 mmol) followed by 2,4-dimethoxybenzylamine (0.25 mL, 1.5mmol). After stirring at 140° C. for 18 h, the reaction was cooled toambient temperature, diluted with EtOAc (100 mL), washed with water (100mL) and brine (100 mL), dried over Na₂SO₄, then filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with hexanes-EtOAc (0-100%) to provide 115B. LCMS(m/z): 444.23 [M+H]⁺; t_(R)=0.90 min. on LC/MS Method A.

Synthesis of(R)-2-((2,7-diaminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(115)

To 115B (14 mg, 0.02 mmol) was added TFA (3 mL). After 4 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH (20 mL) and filtered. After stirringovernight, the solution was concentrated in vacuo to afford 115 as abis-TFA salt. LCMS (m/z): 291.19 [M+H]⁺; t_(R)=0.93 min. on LC/MS MethodA. ¹H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J=2.4 Hz, 1H), 6.69 (d,J=2.4 Hz, 1H), 3.94 (d, J=11.2 Hz, 1H), 3.69 (d, J=11.2 Hz, 1H), 2.06(ddd, J=13.4, 11.0, 5.0 Hz, 1H), 1.91-1.79 (m, 1H), 1.49 (s, 3H), 1.35(td, J=7.4, 4.2 Hz, 4H), 0.92 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d₄) δ −77.58.

Example 116

Synthesis of tert-butyl (R)-(l-hydroxy-2-methylheptan-2-yl)carbamate(116A)

To 111C (315 mg, 2.17 mmol) in THF (30 mL) was added 1M aqueous NaOH(2.2 mL) followed by DIPEA (1.7 mL, 9.76 mmol) and Boc₂O (2.17 g, 9.94mmol). After 18 hours, the mixture was diluted with water (50 mL) andextracted with EtOAc (2×50 mL). The combined organics were washed withbrine (100 mL), dried over Na₂SO₄, and concentrated in vacuo. Thematerial was purified by flash chromatography equipped with an ELSDusing hexane-EtOAc (0-50%) to afford 116A. LCMS (m/z): 245.77 [M+H]⁺;t_(R)=1.15 min. on LC/MS Method A.

Synthesis of tert-butyl (R)-(2-methyl-1-oxoheptan-2-yl)carbamate (116B)

To a solution of 116A (378 mg, 1.54 mmol) in DCM (15 mL) was addedDess-Martin periodinane (981 g, 2.31 mmol). After 90 min, the reactionwas quenched with sat. Na₂S₂O_(3(aq)) (20 mL). The layers were separatedand the aqueous was extracted with DCM (25 mL). The combined organicswere washed with water (50 mL) and brine (50 mE), dried over Na₂SO₄, andconcentrated in vacuo. The material was purified by flash chromatographyequipped with an ELSD using hexane-EtOAc (0-50%) to afford 116B. LCMS(m/z): 143.95 [M+H]⁺; t_(R)=1.23 min. on LC/MS Method A.

Synthesis of tert-butyl(R)-(1-(benzylamino)-2-methylheptan-2-yl)carbamate (116C)

To a solution of 116B (351 mg, 1.44 mmol) in MeOH (6 mL) was addedbenzylamine (0.16 mL, 1.44 mmol). After 18 h, sodium borohydride (91 mg,2.17 mmol) was added to the reaction. After 90 min, the mixture wasconcentrated in vacuo. The residue was diluted with EtOAc (25 mL),washed with 1 M NaOH_((aq)) (20 mL), dried over Na₂SO₄, and concentratedin vacuo to provide crude 116C that was used without furtherpurification. LCMS (m/z): 335.02 [M+H]⁺; t_(R)=0.95 min. on LC/MS MethodA.

Synthesis of tert-butyl(R)-(1-(N-benzylacetamido)-2-methylheptan-2-yl)carbamate (116D)

To a solution of 116C (519 mg, 1.55 mmol) in THF (15 mL) was addedN,N-diisopropylethylamine (0.54 mL, 3.10 mmol) followed by acetylchloride (0.17 mL, 2.33 mmol). After 60 min, the reaction was dilutedwith EtOAc (50 mL), washed with water (30 mL), sat. NaHCO_(3(aq)) (30mL), and brine (30 mL), dried over Na₂SO₄, and concentrated in vacuo.The material was purified by flash chromatography equipped with an ELSDusing hexane-EtOAc (0-100%) to afford 116D. LCMS (m/z): 376.82 [M+H]⁺;t_(R)=1.36 min. on LC/MS Method A.

Synthesis of (R)-N-(2-amino-2-methylheptyl)acetamide (116E)

To a solution of 116D (584 mg, 1.55 mmol) in EtOH (15 mL) was added HClsolution (0.78 mL, 3.10 mmol, 4 M in 2,4-dioxane). The solution was thenpurged with Ar and Pd(OH)₂ (441 mg) were added. The mixture was purgedwith H₂ and heated to 75° C. After 18 h, the mixture was cooled toambient temperature, purged with Ar, filtered, and concentrated in vacuoto provide crude 116E (288 mg) as an HCl salt. LCMS (m/z): 186.96[M+H]⁺; t_(R)=0.52 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(116F)

To a solution of 116E (50 mg, 0.22 mmol) and2,4-dichloropyrido[3,2-d]pyrimidine (45 mg, 0.22 mmol) in THF (3 mL) wasadded N,N-diisopropylethylamine (0.12 mL, 0.67 mmol). After stirring at80° C. for 18 h, the reaction was cooled to ambient temperature, dilutedwith EtOAc (25 mL), washed with water (25 mL) and brine (25 mL), driedover Na₂SO₄, and concentrated in vacuo. The residue was subjected tosilica gel chromatography eluting with hexanes-EtOAc (0-100%) to provide116F. LCMS (m/z): 350.06 [M+H]⁺; t_(R)=1.09 min. on LC/MS Method A

Synthesis of(R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(116G)

To a solution of 116F (58 mg, 0.17 mmol) in 2-MeTHF (3 mL) was addedpotassium carbonate (46 mg, 0.33 mmol) followed by2,4-dimethoxybenzylamine (0.05 mL, 0.33 mmol). After stirring at 85° C.for 18 h, the reaction was cooled to ambient temperature, diluted withEtOAc (25 mL), washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄, then filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with hexanes-EtOAc(20-100%) to provide 116G. LCMS (m/z): 481.27 [M+H]⁺; t_(R)=0.94 min. onLC/MS Method A.

Synthesis of(R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(116)

To 116G (53 mg, 0.11 mmol) was added TFA (3 mL). After 2 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 116 as a TFA salt. LCMS (m/z): 331.25[M+H]⁺; t_(R)=0.72 min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄)δ 8.63 (dd, J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (ddd,J=8.5, 4.4, 1.2 Hz, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.56 (d, J=13.9 Hz,1H), 2.22-2.12 (m, 1H), 1.95 (s, 3H), 1.94-1.85 (m, 1H), 1.54 (s, 3H),1.41-1.30 (m, 6H), 0.88 (t, J=6.3 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d₄) δ −77.86.

Example 117

Synthesis of(R)-N-(2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(117A)

To a solution of 116E (50 mg, 0.22 mmol) and 19B (53 mg, 0.22 mmol) inTHF (3 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.67 mmol).After stirring at 80° C. for 18 h, the reaction was cooled to ambienttemperature, diluted with EtOAc (25 mL), washed with water (25 mL) andbrine (25 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc (0-100%) to provide 117A. LCMS (m/z): 384.01 [M+H]⁺;t_(R)=1.77 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(117B)

To a solution of 117A (33 mg, 0.09 mmol) in 2-MeTHF (3 mL) was addedpotassium carbonate (24 mg, 0.17 mmol) followed by2,4-dimethoxybenzylamine (0.05 mL, 0.17 mmol). After stirring at 85° C.for 18 h, the reaction was cooled to ambient temperature, diluted withEtOAc (50 mL), washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄, then filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with hexanes-EtOAc(0-100%) then EtOAc-MeOH (0-25%) to provide 117B. LCMS (m/z): 515.26[M+H]⁺; t_(R)=1.06 min. on LC/MS Method A.

Synthesis of(R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide(117)

To 117B (38 mg, 0.07 mmol) was added TFA (3 mL). After 2 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 117 as a TFA salt. LCMS (m/z): 632.22[M+H]⁺; t_(R)=0.89 min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d4)δ 8.59 (dd, J=3.5, 2.1 Hz, 1H), 7.92 (d, J=1.9 Hz, 1H), 3.93 (d, J=14.0Hz, 1H), 3.51 (d, J=14.0 Hz, 1H), 2.21-2.10 (m, 1H), 1.96 (s, 3H),1.95-1.87 (m, 1H), 1.54 (s, 3H), 1.35 (dd, J=17.6, 5.4 Hz, 6H), 0.88 (t,J=6.4 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d4) δ −77.80.

Example 118

Synthesis of(R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexanal(118A)

To a solution of 59B (548 mg, 1.29 mmol) in DCM (24 mL) was addedDess-Martin periodinane (829 mg, 1.93 mmol). After 60 min, the reactionwas quenched with sat. Na₂S₂O_(3(aq)) (20 mL), the layers wereseparated, and the aqueous was extract with DCM (25 mL). The combinedorganics were washed with water (50 mL), sat. NaHCO_(3(aq)) (50 mL), andbrine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. Thematerial was purified by flash chromatography using hexane-EtOAc(25-100%) followed by EtOAc-MeOH (0-20%) to afford 118A. LCMS (m/z):424.18 [M+H]⁺; t_(R)=1.04 min. on LC/MS Method A.

Synthesis ofN2-(2,4-dimethoxybenzyl)-N⁴-((R)-2-methyl-1-(((S)-1,1,1-trifluoropropan-2-yl)amino)hexan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine(118B)

To a solution of 118A (70 mg, 0.17 mmol) in MeOH (1 mL) was added(S)-1,1,1-trifluoro-2-propylamine (39 mg, 0.33 mmol, supplied by OakwoodChemical). After 5 h, the reaction was concentrated in vacuo. Theresidue was diluted with THF (2 mL) and lithium aluminum hydridesolution (0.82 mL, 0.82 mmol, 1 M in THF) was added. After 30 min, thereaction was quenched with water (20 mL) and extracted with EtOAc (2×20mL). The combined organics were dried over Na₂SO₄ and concentrated invacuo to afford crude 118B. LCMS (m/z): 521.24 [M+H]⁺; t_(R)=1.26 min.on LC/MS Method A.

Synthesis ofN⁴-((R)-2-methyl-1-(((S)-1,1,1-trifluoropropan-2-yl)amino)hexan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine(118)

To 118B (66 mg, 0.13 mmol) was added TFA (3 mL). After 4 h, the reactionmixture was concentrated in vacuo. The residue was suspended in 50%EtOH_((aq)) (6 mL) and filtered. The solution was purified bypreparative HPLC (Synergi 4u Polar-RP 80A, Axia; 20% aq.acetonitrile-60% aq. acetonitrile with 0.1% TFA, over 20 min. gradient)to afford 122 as a bis-TFA salt. LCMS (m/z): 371.10 [M+H]⁺; t_(R)=1.14min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.62 (dd, J=4.4,1.4 Hz, 1H), 7.87 (dd, J=8.5, 1.4 Hz, 1H), 7.78 (dd, J=8.5, 4.4 Hz, 1H),3.75 (hept, J=7.1 Hz, 1H), 3.64 (d, J=12.8 Hz, 1H), 3.28 (d, J=12.8 Hz,1H), 2.17 (ddd, J=13.6, 11.4, 4.6 Hz, 1H), 1.95 (ddd, J=16.1, 12.3, 4.1Hz, 1H), 1.61 (s, 3H), 1.42 (d, J=6.9 Hz, 3H), 1.40-1.26 (m, 4H), 0.92(t, J=6.9 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −76.47 (d, J=7.1Hz), −77.87.

Unless otherwise stated, LC/MS retention times (tR) reported above weremeasured using LC/MS Method A.

Method for LC/MS HPLC (Method A):

HPLC LC/MS chromatograms were generated using a Thermo Scientific LCQLC/MS system eluting with a Kinetex 2.6u C18 100 A, 5×30 mm HPLC column,using a 1.85 minute gradient elution from 2% aq. acetonitrile-98% aq.acetonitrile with 0.1% formic acid modifier.

Method for LC/MS HPLC (Method B):

HPLC LC/MS chromatograms were generated using a Thermo Scientific LCQLC/MS system eluting with a Kinetex 2.6u C18 100 A, 5×30 mm HPLC column,using a 2.85 minute gradient elution from 2% aq. acetonitrile-98% aq.acetonitrile with 0.1% formic acid modifier.

Biological Example 1—PBMC IFNα, IL12-p40 and TNFα Assays

Certain compounds disclosed herein we tested according to the proceduredescribed below. Additionally, certain reference compounds were preparedand tested along with the compounds of the present disclosure. Forexample, the Compound X was prepared in a manner similar to thatdisclosed in PCT Application Publication No. WO2012/156498 (where thecompound is identified as Compound 72). Compound Y was prepared in amanner similar to that disclosed in PCT Application Publication No.WO2015/014815 (where the compound is identified as Compound 6).

Compounds were dissolved and stored in DMSO (Sigma-Aldrich, St. Louis,Mo.) at 10 mM concentration.

Cells and Reagents

Cryopreserved human PBMCs isolated from healthy donors were purchasedfrom StemCell Technologies (Vancouver, Canada). Cell culture medium usedwas RPMI with L-Glutamine (Mediatech, Manassas, Va.) supplemented with10% fetal bovine serum (Hyclone, GE Healthcare, Logan, Utah) andPenicillin-Streptomycin (Mediatech). Human TNFα, IL12p40, and IFNα2a384-well Assay capture plates, standards, buffers and processingreagents were obtained from MesoScale Discovery Technologies (MSD;Rockville, Md.).

Cryopreserved human PBMCs (1×10e8 cells/ml) were thawed at 37° C. andresuspended in 25 mL warm cell culture medium. The cells were pelletedat 200×g (Beckman Avanti J-E) for 5 min and resuspended in 20 mL offresh culture media. Cells were counted using a Cellometer (NexcelcomBioscience), adjusted to 2×10e6 cells, and incubated for 2 hours in anincubator set at 37° C., 5% CO₂ to recover from cryopreservation.Compounds were serially diluted in DMSO at half-log steps to generate a10-point dose range. Using a Bravo pipette equipped with a 384 well head(Agilent), 0.4 μL of compound was transferred to each well of a 384 wellblack, clear bottom plate (Greiner Bio-One, Germany) containing 30 μL ofcell culture medium. Recovered PBMCs were then dispensed into the assayplate at 50 μL per well (100k cells/well) using the MicroFlowmultichannel dispenser (Biotek). Final DMSO concentration was 0.5%. DMSOwas used as the negative control. The plates were incubated for 24 hoursat 37° C. PBMCs in the assay plate were pelleted by centrifugation(Beckman Avanti J-E) at 200×g for 5 min.

Using a Biomek FX 384 well pipetting station (Beckman), conditionedculture medium (CCM) from the assay plate was transferred to MSD captureplates customized for each cytokine. For IFNα and IL12-p40 detection, 25μL and 20 μL of CCM were added directly to each capture plate,respectively. For TNFα detection, CCM was diluted 1:9 in fresh culturemedium, and 20 μL of diluted CCM was used. Serially diluted calibrationstandards for each cytokine were used to generate standard curves andestablish assay linearity. The plates were sealed and incubatedovernight at 4° C. in a plate shaker (Titer Plate) set at 200 rpm. Onthe following day, antibodies specific for each cytokine were diluted1:50 in MSD Diluent 100 antibody dilution buffer. Diluted antibodieswere added to corresponding capture plates at 10 μL/well, and incubatedat RT for 1-2 hrs in the shaker. The plates were washed with PBST buffer(3×, 60 μl/well) using a Biotek Multiflow plate washer. MSD Read Bufferdiluted to 2× in deionized water and 35 μL/well was added via Biomek FXinstrument. The plates were read immediately in a MSD6000 reader. Datawere normalized to positive and negative controls in each assay plate.AC₅₀ values represent compound concentrations at half-maximal effectbased on normalized percent activation and calculated by non-linearregression using Pipeline Pilot software (Accelrys, San Diego, Calif.).

Results of the cytokine profiling assay are reported in Table 1, Table2, and Table 3 below.

TABLE 1 TNFα AC₅₀ IL12p40 AC₅₀ IFNα AC₅₀ Compound (μM) (μM) (μM)  1B 3.92 2.7  2B 5.4 2.8 4.3  3B 29.4 15.5 14.5  4B 9.1 5.4 5.9  5B >50 >50 41 6B >50 >50 >50  7 >50 >50 34  8 20.2 19.4 >50  9 1.9 1.1 7.2 10 29.223.8 >50 11 10.1 6 6.9 12 >50 >50 >50 13 >50 >50 >50 14 1.1 0.94 1.6 151.6 1.2 >200 16 >50 >50 >50 17 >50 >50 >50 18F 16.1 15.2 30.6 19E 3.32.5 21.6 20 3.2 2.8 5.4 21 3.1 2.3 4.8 22 >50 >50 35.9 23C 24.7 25.7 >5024D 3.4 3.1 18.4 25E 20 19.7 12.3 26E 2.3 1.7 13.5 27C 0.52 0.42 2 2828.6 28.2 45 29 18.3 15.5 3.9 30B 10.6 8.6 >50 31 4.7 4.7 32.932 >50 >50 >50 33 0.92 0.85 5.9 34 12.2 10.9 >50 35 39.4 22.6 >50 3621.5 10.8 >50 37 >50 >50 >50 38C >50 >50 >50 39C >50 41.5 >50 40C 0.940.87 2.4 41 11 9.1 13 42B 1.1 0.9 3.6 43C 1.1 1 10.9 44 3 2.4 >50 45 1.61.3 8.3 46C 28.6 28.5 >50 47B 2.70 2.0 >50 48 0.85 0.71 0.57

TABLE 2 TNFα AC₅₀ IL12p40 AC₅₀ IFNα AC₅₀ Compound (μM) (μM) (μM) X 1.20.97 7.1 Y 11.2 13.0 >50

TABLE 3 TNFα AC₅₀ IL12p40 AC₅₀ IFNα AC₅₀ Compound (μM) (μM) (μM) 49 22.418.1 41.6 50 26.9 23.1 >50 51 0.37 0.33 >200 52 3.2 3.6 >50 53 0.26 0.283.9 54 34.0 42.5 >50 55 23.9 21.5 28.8 56 3.6 3.4 1.9 57 11.0 9.7 >50 583.9 3.8 4.1 59 0.18 0.17 15.0 60 2.6 2.3 7.9 61 0.02 0.02 42.1 62 1.00.91 >50 63 0.41 0.43 22.4 64 3.1 3.2 37.9 65 0.11 0.09 >50 66 0.04 0.031.6 67 6.3 3.9 23.0 68 11.1 14.2 >50 69 31.0 30.8 34.8 70 3.3 2.7 >50 712.6 2.7 >50 72 7.2 7.0 >50 73 1.3 1.3 >50 74 9.1 9.6 >50 75 4.0 3.3 20.376 36.9 31.8 36.9 77 43.6 43.6 43.6 78 16.0 14.2 >50 79 9.1 11.5 >50 802.7 2.4 >50 81 7.6 7.8 >50 82 16.6 14.3 >50 83 1.7 1.8 43.1 84 3.03.9 >50 85 0.86 0.80 4.0 86 2.9 2.4 37.4 87 5.0 4.5 >50 88 0.4 0.37 35.689 2.2 1.7 >50 90 0.86 0.62 7.8 91 2.0 1.9 >50 92 4.3 4.7 >50 93 0.440.40 >50 94 1.0 0.7 2.2 95 0.15 0.15 >50 96 1.1 1.0 2.8 97 0.14 0.1326.0 98 0.24 0.23 134 99 3.4 3.6 >50 100 3.8 3.5 4.6 101 0.10 0.11 >50102 0.81 0.76 >50 103 3.3 2.6 10.3 104 2.1 1.9 4.2 105 3.5 3.4 >50 10613.8 10.2 >50 107 2.8 1.8 >50 108 38.7 22.0 >50 110 32.6 32.6 32.6 1110.61 0.47 19.8 112 0.36 0.33 >50 113 12.5 13.6 >50 114 0.34 0.20 34.1115 0.024 0.027 9.0 116 0.036 0.11 >50 117 0.37 0.33 >50 118 9.3 9.1 >50

In certain embodiments, certain compounds disclosed herein have an AC₅₀for TNFα that is less than about 100 μM, less than about 50 μM, lessthan about 40 μM, less than about 30 μM, less than about 25 μM, lessthan about 20 μM, less than about 15 μM, less than about 10 μM, lessthan about 5 μM, less than about 4 μM, less than about 3 μM, less thanabout 2 μM, or less than about 1 μM. In certain embodiments, certaincompounds disclosed herein have an AC₅₀ for TNFα that is greater thanabout 25 μM or greater than about 50 μM. In certain embodiments, certaincompounds disclosed herein have an AC₅₀ for TNFα that is less than about0.75 μM, less than about 0.5 μM, or less than about 0.25 μM. As isunderstood by those of skill in the art, the induction of TNFα isassociated with agonism of TLR8.

In certain embodiments, certain compounds disclosed herein have an AC₅₀for IL12p40 that is less than about 100 μM, less than about 50 μM, lessthan about 40 μM, less than about 30 μM, less than about 25 μM, lessthan about 20 μM, less than about 15 μM, less than about 10 μM, lessthan about 5 μM, less than about 4 μM, less than about 3 μM, less thanabout 2 μM, less than about 1 μM, or less than about 0.5 μM. In certainembodiments, certain compounds disclosed herein have an AC₅₀ for IL12p40that is greater than about 25 μM or greater than about 50 μM. As isunderstood by those of skill in the art, the induction of IL12p40 isassociated with agonism of TLR8.

In certain embodiments, certain compounds disclosed herein have an AC₅₀for IFNα that is less than about 200 μM, less than about 100 μM, lessthan about 50 μM, less than about 40 μM, less than about 30 μM, lessthan about 25 μM, less than about 20 μM, less than about 15 μM, lessthan about 10 μM, less than about 5 μM, less than about 4 μM, less thanabout 3 μM, less than about 2 μM, or less than about 1 μM. In certainembodiments, certain compounds disclosed herein have an AC₅₀ for IFNαthat is greater than about 25 μM, greater than about 50 μM, greater thanabout 100 μM, greater than about 150 μM, or greater than about 200 μM.As is understood by those of skill in the art, the induction of IFNα isassociated with agonism of TLR7.

In certain embodiments, the compounds of the present disclosure areselective TLR8 agonists. Compounds that are selective TLR8 agonistsproduce a cytokine effect associated with TLR8 induction (e.g. TNFα andIL12p40) at a lower concentraction than that associated with TLR7induction (e.g. IFNα). In certrain embodiments, when analyzed in thecytokine profiling assay, the compounds induce IFNα at a concentrationat least about 2 times higher than the concentration at which TNFαand/or IL12p40 are induced; in certain embodiments the compounds induceIFNα at a concentration at least about 4 times higher than theconcentration at which TNFα and/or IL12p40 are induced; in certainembodiments the compounds induce IFNα at a concentration at least about6 times higher than the concentration at which TNFα and/or IL12p40areinduced; in certain embodiments the compounds induce IFNα at aconcentration at least about 8 times higher than the concentration atwhich TNFα and/or IL12p40 are induced; in certain embodiments thecompounds induce IFNα at a concentration at least about 10 times higherthan the concentration at which TNFα and/or IL12p40 are induced; incertain embodiments the compounds induce IFNα at a concentration atleast about 20 times higher than the concentration at which TNFα and/orIL12p40 are induced; in certain embodiments the compounds induce IFNα ata concentration at least about 30 times higher than the concentration atwhich TNFα and/or IL12p40 are induced; in certain embodiments thecompounds induce IFNα at a concentration at least about 40 times higherthan the concentration at which TNFα and/or IL12p40 are induced; incertain embodiments the compounds induce IFNα at a concentration atleast about 50 times higher than the concentration at which TNFα and/orIL12p40 are induced; in certain embodiments the compounds induce IFNα ata concentration at least about 75 times higher than the concentration atwhich TNFα and/or IL12p40 are induced; in certain embodiments thecompounds induce IFNα at a concentration at least about 100 times higherthan the concentration at which TNFα and/or IL12p40 are induced; incertain embodiments the compounds induce IFNα at a concentration atleast about 125 times higher than the concentration at which TNFα and/orIL12p40 are induced; in certain embodiments the compounds induce IFNα ata concentration at least about 150 times higher than the concentrationat which TNFα and/or IL12p40 are induced; in certain embodiments thecompounds induce IFNα at a concentration at least about 175 times higherthan the concentration at which TNFα and/or IL12p40 are induced; and incertain embodiments the compounds induce IFNα at a concentration atleast about 200 times higher than the concentration at which TNFα and/orIL12p40 are induced.

As is understood by those of skill in the art, each compound of thepresent disclosure may have AC₅₀ values for each cytokine tested (e.g.TNFα, IL12p40, and IFNα) that include various combinations of the rangesdisclosed above. As such, the present disclosure provides for suchcombinations. Further, the ability of any particular compound or groupof compounds to selectively modulate a particular receptor can beextrapolated from the AC₅₀ data disclosed herein. One of skill in theart will necessarily appreciate the various selectivities of anyparticular compound or group of compounds.

Biological Example 2—Efficacy Study in WHV-Infected Woodchucks

The in vivo antiviral efficacy of a compound disclosed herein wasevaluated in the woodchuck model of CHB. Woodchucks chronically infectedwith woodchuck hepatitis virus (WHV) (n=23) were stratified into aplacebo group (n=1), a 1 mg/kg dose group (n=6), and a 3 mg/kg dosegroup (n=6) based on gender and baseline antiviral parameters. Animalswith high gamma glutamyltransferase (GGT) levels (that correlate with anincreased risk of hepatocellular carcinoma (HCC)) and/or with livertumors observed at the pre-study biopsy screening were included in theplacebo group. This stratification was performed so that adverse events(including death) associated with HCC would not confound safetyassessment of the dosing groups receiving a compound disclosed herein.The plan for this ongoing study was as follows: animals were dosed POonce a week for 8 weeks with compound or vehicle, followed by afollow-up period of 24 weeks. The animals were monitored for safety andin-life parameters (blood chemistry/hematology/temperature),pharmacokinetics (serum PK), pharmacodynamics (whole blood MARCO mRNAand WHV-specific T cell responses) and antiviral efficacy (serum WHVDNA, woodchuck hepatitis surface antigen (WHsAg) and anti-sAgantibodies, and liver WHV cccDNA, DNA and mRNA).

Interim analysis of this ongoing study revealed that animals dosed withvehicle or 1 mg/kg for 8 weeks did not have any changes in serum WHV DNAor WHsAg levels. In contrast, there was a strong decline in both viralendpoints in 4/6 animals in the 3 mg/kg dose group. Serum WHV DNA andWHsAg levels for three of these animals did not revert at week 12, fourweeks after cessation of treatment. Of note, three animals haddetectable levels of anti-WHsAg starting at week 4 that were stillincreasing, stabilizing, or decreasing by week 12. These interim datashow that a compound of the present disclosure has antiviral andanti-HBsAg activity as well as the ability to induce anti-HBsAg antibodyin vivo in the woodchuck model of CHB.

Biological Example 3—Off Target Toxicity

To assess potential off-target toxicity of certain compounds disclosedherein, the in vitro cytotoxicity of those compounds was profiled usinga panel of 5cell lines with various tissue origins. Compoundcytotoxicity was examined in hepatoma-derived Huh-7 and HepG2 cells,prostate carcinoma-derived PC-3 cells, lymphoma derived MT-4 cells and anormal diploid lung cell line MRC-5. HepG2 and PC-3 cells used wereadapted to grow in glucose-free galactose-containing medium. These cellshave a relatively higher sensitivity to inhibitors of mitochondrialoxidative phosphorylation compared to the same cells maintained instandard glucose-containing culture medium (Marroquin et al., Toxicol.Sci. 2007; 97 (2):539-47). Cell viability was determined by measuringintracellular ATP levels following five days of continuous incubationwith test compounds.

Cell Cultures

The human hepatoma Huh-7 cell line was obtained from ReBLikon GmbH(Mainz, Germany) {20879}. The MT-4 cell line (HTLV-1 transformed, humanT lymphoblastoid cells) was obtained from the NIH AIDS Reagent program(Bathesda, Md.). The human hepatoblastoma cell line HepG2, humanprostate carcinoma cell line PC-3, and normal fetal lung derived MRC-5cells were obtained from the American Type Culture Collection (ATCC,Manassas, Va.).

Huh-7 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM)supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, Utah), 1%non-essential amino acids (Gibco, Carlsbad, Calif.). PC-3 and HepG2cells were adapted to grow in 0.2% galactose-containing, glucose-freeDulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetalbovine serum (FBS, Hyclone, Logan, Utah), 1% non-essential amino acids(Gibco, Carlsbad, Calif.), 1% Pyruvate (Cellgro), 1% Glutamax(Invitrogen, Carlsbad, Calif.). Galactose-adapted cells were maintainedin the same culture medium. MRC-5 cells were maintained in Eagle'sMinimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum(FBS, Hyclone, Logan, Utah). MT-4 cells were maintained in RPMI-1640supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, Utah).All cell culture media were also supplemented with 100 Units/mLpenicillin, 100 μg/mL streptomycin (Gibco).

Cytotoxicity Assays

Using a Biotek uFlow Workstation (Biotek, Winooski, Vt.), 1500 HepG2,1500 PC-3, 500 Huh7 or 1500 MRC-5 cells in 90 μL of culture media weredispensed into each well of black polystyrene tissue culture-treated384-well plates. Plated cells were incubated for 24 hours in anincubator at 37° C., 5% CO₂ and 90% humidity. Compound serial dilutionswere performed in 100% DMSO in 384-well polypropylene (high recovery)plates on a Biomek FX Workstation (Beckman Coulter, Fullerton, Calif.).After 3-fold serial dilutions, 0.4 μL of compounds were transferred into384-well plates containing cells using a Velocity 11 system equippedwith a Bravo 384-well pipettor. The DMSO concentration in the finalassay plates was 0.44% (v/v). Cells were incubated with compound(s) forfive days at 37° C. Puromycin (44 M final concentration) and DMSO(0.44%, v/v) were used as a positive and negative controls, respectively

At the end of the incubation period the cytotoxicity assay was performedas follows: Media from 384-well cell culture plates were aspirated witha Biotek EL405 plate-washer (Biotek) and cells were washed with 100 μLPBS once. Twenty microliters of Cell Titer Glo (Promega, Madison, Wis.)was added to each well of the plates with a Biotek uFlow liquiddispenser. Plates were incubated for 15 minutes at room temperaturebefore luminescence was measured with a Perkin Elmer Envision PlateReader (Perkin Elmer, Waltham, Mass.).

For the MT-4 cytotoxicity assay, 0.4 μL of serially diluted compoundswere added to 40 μl of cell maintenance media in 384-well black, solidbottom plate using a Biomek FX workstation (Beckman Coulter). Twothousand cells in 35 μL were added to each well using a Biotek uFlowWorkstation (Biotek). Each assay plate contained 10 μM Puromycin (finalconcentration) and 0.5% DMSO in RPMI-1640 as positive and negativecontrols, respectively. Assay plates were incubated for five days at 37°C. in an incubator set at 5% CO2 and 90% humidity. After five days, 22μL of Cell Titer Glo reagent (Promega) was added to the assay plateswith a Biotek uFlow Workstation. Plates were subsequently placed on aPerkin Elmer Envision Plate Reader for five minutes before theluminescence signal was read.

Data Analysis

CC₅₀ values were defined as the compound concentration that caused a 50%decrease in luminescence signal, and were calculated by non-linearregression using Pipeline Pilot software by applying a four parameterfit equation (Accelrys, San Diego, Calif.). Results are summarized inthe table below. Individual CC50 values are listed as μM concentrations.

CC50 CC50 CC50 CC50 GALHEPG2 GALPC3 HUH7 MRC5 CC50 Compound CTG 5D CTG5D CTG 5D CTG 5D (MT4) 15 1.23 0.69. 10.70 7.60 8.62 44 1.07 0.52 9.643.72 1.97 59 8.88 5.20 35.39 40.31 31.40 98 6.70 4.53 21.90 24.42 16.1751 44.44 37.23 44.44 44.44 57.14 102 27.42 19.08 44.44 44.44 57.14 6144.44 44.44 44.44 44.44 212.39 62 44.44 29.74 44.44 44.44 19.23 93 7.733.63 44.44 38.80 18.55 64 3.56 1.55 10.36 6.97 0.79 101 44.44 44.4444.44 44.44 50.0 65 44.44 44.44 44.44 44.44 50.0 95 28.06 16.76 31.3444.44 44.11 97 33.01 27.51 44.44 44.44 50.0 X 7.85 6.79 16.91 20.9553.77 Y 0.19 0.18. 2.31 0.95 1.42As will be appreciated by one of skill in the art, a high ratio of CC₅₀from the cytotoxicity assays to AC₅₀ (e.g. of TNFα and/or IL12p40)indicates potential good safety margins in vivo.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure.

1.-102. (canceled)
 103. A compound of Formula (IVd),

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of hydrogen, halogen, C₁₋₆ alkyl, CN, andOR^(a), wherein C₁₋₆ alkyl is optionally substituted with 1 to 5 R²⁰groups; R² is selected from the group consisting of hydrogen, halogen,C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl is optionally substitutedwith 1 to 5 R²⁰ groups; R³ is selected from the group consisting ofhydrogen, halogen, C₁₋₆ alkyl, CN, and OR^(a), wherein C₁₋₆ alkyl isoptionally substituted with 1 to 5 R²⁰ groups; R¹¹ is selected from thegroup consisting of hydrogen, and C₁₋₂ alkyl; R^(12a) is selected fromthe group consisting of hydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl; R¹³ isC₃₋₆ alkyl; each R²⁰ is independently selected from the group consistingof halogen, CN, —NR^(a)R^(b), and OR^(a); and each R^(a) and R^(b) isindependently selected from the group consisting of hydrogen and C₁₋₃alkyl, wherein each C₁₋₃ alkyl is optionally substituted with 1 to 3substituents independently selected from halogen, hydroxyl, amino, andC₁₋₆ haloalkyl.
 104. The compound of claim 103, or a pharmaceuticallyacceptable salt thereof, wherein: R¹ is selected from the groupconsisting of hydrogen, halogen, and C₁₋₃ alkyl, wherein C₁₋₃ alkyl isoptionally substituted with 1 to 5 halogen groups; R² is selected fromthe group consisting of hydrogen, halogen, C₁₋₃ alkyl, CN and OR^(a),wherein C₁₋₃ alkyl is optionally substituted with 1 to 5 halogen groups;and R³ is selected from the group consisting of hydrogen, halogen, andC₁₋₃ alkyl.
 105. The compound of claim 103, or a pharmaceuticallyacceptable salt thereof, wherein: R¹ is selected from the groupconsisting of hydrogen, methyl, fluoro, chloro, and CF₃; R² is selectedfrom the group consisting of hydrogen, methyl, ethyl, fluoro, chloro,bromo, CF₃, CN, OH, OMe, and OEt; and R³ is selected from the groupconsisting of hydrogen, methyl, fluoro, and chloro.
 106. The compound ofclaim 103, or a pharmaceutically acceptable salt thereof, wherein: R¹ ishydrogen; R² is selected from the group consisting of hydrogen andfluoro; and R³ is selected from the group consisting of hydrogen andmethyl.
 107. The compound of claim 103, or a pharmaceutically acceptablesalt thereof, wherein R¹¹ is methyl.
 108. The compound of claim 103, ora pharmaceutically acceptable salt thereof, wherein R¹¹ is hydrogen.109. The compound of claim 103, or a pharmaceutically acceptable saltthereof, wherein each R^(a) and R^(b) is independently selected from thegroup consisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom hydroxyl and amino.
 110. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein R¹³ is propyl, butylor pentyl.
 111. The compound of claim 103, or a pharmaceuticallyacceptable salt thereof, wherein R¹³ is propyl or butyl.
 112. Thecompound of claim 103, or a pharmaceutically acceptable salt thereof,wherein: R¹¹ is methyl; and R¹³ is selected from the group consisting ofpropyl, butyl and pentyl.
 113. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen orfluoro; and R¹³ is selected from the group consisting of propyl andbutyl.
 114. The compound of claim 103, or a pharmaceutically acceptablesalt thereof, wherein R¹ is selected from the group consisting ofhydrogen, halogen, and C₁₋₃ alkyl; R² is selected from the groupconsisting of hydrogen, halogen, and C₁₋₃ alkyl; R³ is selected from thegroup consisting of hydrogen, halogen, and C₁₋₃ alkyl; R¹¹ is C₁₋₂alkyl; R^(12a) is selected from the group consisting of hydrogen, C₁₋₂alkyl and C₁₋₃ haloalkyl; R¹³ is C₃₋₆ alkyl; and each R^(a) and R^(b) isindependently selected from the group consisting of hydrogen and C₁₋₃alkyl, wherein each C₁₋₃ alkyl is optionally substituted with 1 to 3substituents independently selected from hydroxyl and amino.
 115. Thecompound of claim 103, or a pharmaceutically acceptable salt thereof,wherein the compound of Formula (IVd) has the structure:

wherein R² is selected from the group consisting of hydrogen, methyl,fluoro, and chloro; R³ is selected from the group consisting of hydrogenand methyl; R^(12a) is selected from the group consisting of hydrogen,C₁₋₂ alkyl and C₁₋₃ haloalkyl; R¹³ is C₃₋₆ alkyl; and R^(b) is methyl orethyl, each optionally substituted with hydroxyl or amino.
 116. Thecompound of claim 103, or a pharmaceutically acceptable salt thereof,wherein the compound of Formula (IVd) has the structure:

wherein R¹³ is C₃₋₆ alkyl.
 117. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (IVd) has the structure:

wherein R² is selected from the group consisting of hydrogen, Cl, and F;and R¹³ is C₃₋₆ alkyl.
 118. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (IVd) has the structure:

wherein R³ is selected from the group consisting of hydrogen and methyl;and R¹³ is C₃₋₆ alkyl.
 119. The compound of claim 103, or apharmaceutically acceptable salt thereof, having the structure:

wherein R¹ is selected from the group consisting of hydrogen, halogen,and C₁₋₃ alkyl; R² is selected from the group consisting of hydrogen,halogen, and C₁₋₃ alkyl; R³ is selected from the group consisting ofhydrogen, halogen, and C₁₋₃ alkyl; R^(12a) is selected from the groupconsisting of hydrogen, C₁₋₂ alkyl and C₁₋₃ haloalkyl; R¹³ is C₃₋₆alkyl; and each R^(a) and R^(b) is independently selected from the groupconsisting of hydrogen and C₁₋₃ alkyl, wherein each C₁₋₃ alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom halogen, hydroxyl, amino, and C₁₋₆ haloalkyl.
 120. The compound ofclaim 103, or a pharmaceutically acceptable salt thereof, wherein R¹ ishydrogen, halogen, or C₁₋₆ alkyl optionally substituted with 1 to 5 R²⁰groups.
 121. The compound of claim 103, or a pharmaceutically acceptablesalt thereof, wherein R¹ is hydrogen, halogen, or C₁₋₃ alkyl optionallysubstituted with 1 to 5 halogens.
 122. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen, Cl,CH₃, or CF₃.
 123. The compound of claim 103, or a pharmaceuticallyacceptable salt thereof, wherein R² is hydrogen, halogen, —OH, CN, orC₁₋₆ alkyl optionally substituted with 1 to 5 R²⁰ groups.
 124. Thecompound of claim 103, or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen, halogen, —OH, CN or C₁₋₃ alkyl optionallysubstituted with 1 to 5 halogens.
 125. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen, CH₃,—OH, —CF₃, —CH₂CH₃, F, Br, Cl, or CN.
 126. The compound of claim 103, ora pharmaceutically acceptable salt thereof, wherein R³ is hydrogen,halogen, or C₁₋₆ alkyl optionally substituted with 1 to 5 R²⁰ groups.127. The compound of claim 103, or a pharmaceutically acceptable saltthereof, wherein R³ is hydrogen, halogen, or C₁₋₃ alkyl optionallysubstituted with 1 to 5 R²⁰ groups.
 128. The compound of claim 103, or apharmaceutically acceptable salt thereof, wherein R³ is hydrogen, Cl, orCH₃.
 129. The compound of claim 103, selected from

or a pharmaceutically acceptable salt thereof.
 130. A pharmaceuticalcomposition for treating or preventing a disease or condition responsiveto the modulation of TLR-8 comprising a compound of claim 103, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 131. The pharmaceutical composition of claim 130,further comprising one or more additional therapeutic agents selectedfrom the group consisting of HBV DNA polymerase inhibitors, toll-likereceptor 7 modulators, toll-like receptor 8 modulators, toll-likereceptor 7 and 8 modulators, toll-like receptor 3 modulators, interferonalpha ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilininhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBVviral entry inhibitors, NTCP inhibitors, antisense oligonucleotidetargeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virusE antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodiesincluding HBV antibodies targeting the surface antigens of the hepatitisB virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBVcore or capsid protein inhibitors), stimulators of retinoicacid-inducible gene 1, stimulators of NOD2, recombinant thymosin alpha-1and hepatitis B virus replication inhibitors, hepatitis B surfaceantigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, HIVprotease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors ofreverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, pharmacokinetic enhancers,selected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-la(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ),Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha,Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN,Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano,Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow),peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon,Urifron, interferon alfa-2b (Changchun Institute of BiologicalProducts), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2),recombinant human interleukin-2, Layfferon, Ka Shu Ning, Shang Sheng LeiTai, Intefen, Sinogen, Fukangtai, Alloferon, and celmoleukin, andcombinations thereof.
 132. A method of treating a hepatitis B viralinfection, comprising administering to an individual in need thereof atherapeutically effective amount of a compound of claim 103, or apharmaceutically acceptable salt thereof.
 133. The method of claim 132,further comprising administering one or more additional therapeuticagents selected from the group consisting of HBV DNA polymeraseinhibitors, toll-like receptor 7 modulators, toll-like receptor 8modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3modulators, interferon alpha ligands, HBsAg inhibitors, compoundstargeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBVprophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNAinhibitors, HBV antibodies including HBV antibodies targeting thesurface antigens of the hepatitis B virus, thymosin agonists, cytokines,nucleoprotein inhibitors (HBV core or capsid protein inhibitors),stimulators of retinoic acid-inducible gene 1, stimulators of NOD2,recombinant thymosin alpha-1 and hepatitis B virus replicationinhibitors, hepatitis B surface antigen (HBsAg) secretion or assemblyinhibitors, IDO inhibitors, and combinations thereof, selected from thegroup consisting of adefovir (Hepsera®), tenofovir disoproxilfumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate(Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®),Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin.